JPH0653738B2 - Thiazolidine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Conventionally, it has been reported that thiazolidine derivatives have blood lipid and blood glucose lowering action in JP-A-55-22636 and Ch.
Em. Pharm. Bull. 30 , 3580 (1982).

The present inventors have conducted extensive studies on thiazolidine derivatives for the purpose of developing drugs for circulatory organs, and a novel compound having the following general formula (I) has an effect of improving lipid metabolism in blood, an effect of improving blood glucose metabolism and aldose-reduced oxygen inhibition. The present invention, which has been found to have an action and to have extremely low toxicity, has been completed.

The novel thiazolidine derivative of the present invention has the general formula A compound represented by or a salt thereof is included.

In the above formula (I), R ¹ represents a hydrogen atom, an alkyl group, an aralkyl group which may have a substituent or a cycloalkyl group which may have a substituent, and R ² represents a hydrogen atom or an alkyl. R ³ and R ³ ′ described below are the same or different and represent a hydrogen atom or a hydroxyl-protecting group, R ⁴ is a hydrogen atom, an alkyl group, an aralkyl group which may have a substituent, a substituent Represents an optionally substituted cycloalkyl group, an optionally substituted aryl group or an alkoxy group, R ⁵ represents a hydrogen atom, an alkyl group or an alkoxy group, and R ⁶ and R ⁷ are the same or differently represent a hydrogen atom or an alkyl group, R ⁸ and R ⁹ are the same or different and represent a hydrogen atom or an optionally substituted alkyl group, Ar may have a substituent Indicates the valency of the aromatic ring group or substituted or divalent be heteroaromatic ring group, W is ^'in group (wherein, R ^3' methylene group, a carbonyl group, the formula> CH-OR 3 is above The formula> = N-OV group (in the formula, V represents a hydrogen atom, an alkyl group which may have a substituent or an alkyl group which may have a substituent). Or a formula> = N-OR ³ ′ _a group (in the formula, R ³ ′ _a
Represents a hydroxyl-protecting group for R ³ ′ described above. ) Or a double bond may be formed with U described later, wherein U represents a single bond or a methylene group, or W
Form a double bond together with, or W is a carbonyl group, formula>
= N-OV group or the formula> = ^N-OR 3 _'a group (wherein,
V and R ³ ′ _a have the same meanings as described above. ), A double bond may be formed together with R ¹ and n is 1
To Y, Y represents an oxygen atom or an imino group, Z represents an oxygen atom or an imino group, or W
When is a methylene group, it may represent a sulfur atom.

However, in the formula (I), R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, and R ³ and R ³ ′ described later are the same or different and are a hydrogen atom, an aliphatic lower acyl group, an aliphatic group. A cyclic acyl group, an aromatic acyl group which may have a substituent, a heterocyclic acyl group, an aromatic aliphatic acyl group which may have a substituent, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group, Show, R
⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R ⁶ , R ⁷ , R
⁸ and R ⁹ represent a hydrogen atom, Ar represents a p-phenylene group, W represents a methylene group, a carbonyl group or a formula = C.
H-OR ³ ′ (R ³ ′ has the same meaning as described above), U represents a methylene group, and n
Represents an integer of 1 to 3, Y represents an oxygen atom or an imino group, Z represents an oxygen atom when W represents a methylene group,
A sulfur atom or an imino group, Z is or oxygen atom in the case of the proximal W is represented by a carbonyl group, or a group of the formula ^{= CH-OR 3 '(R} 3' have the same meanings as defined above.) Indicates an imino group; except cases.

In the general formula (I), R ¹ is a hydrogen atom, a linear or branched alkyl group having 1 to 25 carbon atoms, an optionally substituted aralkyl group having 7 to 10 carbon atoms, or It represents a cycloalkyl group having 5 to 8 carbon atoms which may have a substituent, R ² represents a hydrogen atom or a linear or branched alkyl group having 1 to 12 carbon atoms, and R ³ represents hydrogen. Having a carboxy group, a lower alkoxycarbonyl group, a carbamoyl group, a mono- or dialkyl-substituted carbamoyl group, a 5- or 6-membered cyclic aminocarbonyl group, a hydroxyl group, a lower alkoxy group, or an aliphatic or aromatic acyloxy group as an atom or a substituent May be a linear or branched alkyl group having 1 to 10 carbon atoms, or may have an unsaturated bond, or may have a substituent, 1 carbon atom. 23 aliphatic acyl group, alicyclic acyl group, optionally substituted aromatic acyl group, heterocyclic acyl group, optionally substituted aromatic aliphatic acyl group, alkoxycarbonyl group Represents an aralkyloxycarbonyl group or a carbamoyl group which may be substituted with an alkyl group, an aralkyl group or an aryl group, R
³ ′ represents a hydrogen atom or the acyl group in R ³ , and R ⁴ represents a hydrogen atom, a linear or branched alkyl group having 1 to 20 carbon atoms, or a carbon number which may have a substituent. 7 to 10 aralkyl group, optionally substituted cycloalkyl group having 5 to 8 carbon atoms, optionally substituted aryl group, or linear or branched carbon atom number 1 to 12 represents an alkoxy group, R ⁵ is a hydrogen atom,
A linear or branched alkyl group having 1 to 20 carbon atoms or a linear or branched alkoxy group having 1 to 12 carbon atoms, wherein R ⁶ and R ⁷ are the same or different, and are hydrogen. An atom or a linear or branched alkyl group having 1 to 4 carbon atoms, wherein R ⁸ and R ⁹ are the same or different and each is a hydrogen atom or a substituent having the same meaning as R ³ described above. Represents an alkyl group having 1 to 10 carbon atoms, Ar represents a divalent aromatic ring group which may have a substituent or a divalent heteroaromatic ring group which may have a substituent, and W represents Methylene group, carbonyl group, formula> = CH-O
R ³ ′ group (wherein R ³ ′ has the same meaning as described above), formula> = N—OV group (in the formula, V is a hydrogen atom, and has the same meaning as in R ³ described above). A linear or branched carbon number 1 to 10 which may have a substituent
7 carbon atoms which may have an alkyl group or a substituent
No. 11 to No. 11 aralkyl groups are shown. ) Or the formula> = N-O
-R ³ ′ _a (wherein R ³ ′ _a represents a group having the same meaning excluding the hydrogen atom in R ³ ′ described above) or may form a double bond with U described later. , U
Represents a single bond or a methylene group, or forms a double bond with W, and W is a carbonyl group, and the formula> =
When it represents an N—OV group or a formula> = N—OR ³ ′ _a group, it may form a double bond with R ¹ , n represents an integer of 1 to 10, Y represents an oxygen atom or an imino group. , Z may be an oxygen atom or an imino group, or may be a sulfur atom when W is a methylene group.

However, in the formula (I), R ¹ and R ² are the same or different and each represent a hydrogen atom or a linear or branched lower alkyl group having 1 to 5 carbon atoms, and R ³ and R ³ ′ described later Is the same or different and is a hydrogen atom, an aliphatic acyl group having 2 to 6 carbon atoms which may have an unsaturated bond, an alicyclic acyl group, an aromatic acyl group which may have a substituent, a heterocyclic group. A cyclic acyl group, an aromatic aliphatic acyl group which may have a substituent, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group, wherein R ⁴ and R ⁵ are the same or different and each is a hydrogen atom, a straight chain or A branched C 1-5 lower alkyl group or a lower alkoxy group is shown, R ⁶ , R ⁷ , R ⁸ and R ⁹ are hydrogen atoms, Ar is a p-phenylene group, and W is a methylene group. , Carbonyl group Or formula ^{= CH-OR 3 '(R} 3' is. Showing the same meanings as defined above) a group represented by
U represents a methylene group, n represents an integer of 1 to 3, and Y
Represents an oxygen atom or an imino group, Z represents an oxygen atom, a sulfur atom or an imino group when W represents a methylene group, Z represents W is a carbonyl group or a formula ═CH—OR ³ ′.
When the group represented by (R ³ ′ has the same meaning as described above), it represents an oxygen atom or an imino group; except the case.

In the general formula (I), when R ¹ represents an alkyl group, R ¹ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl,
Hexyl, isohexyl, neohexyl, 1-methylpentyl, 3-methylpentyl, 1,3-dimethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl,
Octyl, 1-methylheptyl, 2-ethylhexyl,
5,5-dimethylhexyl, nonyl, decyl, 1-methylnonyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl, dodecyl, tridecyl, tetradecyl, pentadecyl,
3,7,11-trimethyldodecyl, hexadecyl,
4,8,12-trimethyltridecyl, heptadecyl,
Octadecyl, Nonadecyl, Eicosyl, 3,7,1
Examples thereof include linear or branched ones having 1 to 25 carbon atoms such as 1,15-tetramethylhexadecyl, docosyl or pentacosyl; R ¹ represents an optionally substituted aralkyl group. In this case, examples of R ¹ include those having 7 to 10 carbon atoms such as benzyl, phenethyl, 3-phenylpropyl, and 4-phenylbutyl.
Examples of the substituent on the benzene ring include a lower alkyl group such as methyl, ethyl and propyl, a lower alkoxy group such as methoxy, ethoxy and propoxy, or a halogen atom such as fluorine, chlorine, bromine and iodine; R ¹
Represents an optionally substituted cycloalkyl group,
Examples of the cycloalkyl group include those having 5 to 8 carbon atoms such as cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups, and the substituents thereof include lower alkyl groups such as methyl, ethyl and propyl.

When R ² represents an alkyl group, examples of R ² include those having 1 to 12 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, octyl and dodecyl.

When R ³ and R ⁸ , R ⁹ and V described later represent an alkyl group which may have a substituent, R ³ , R ⁸ and R ⁹
And the same or different as V, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert
-A linear or branched alkyl group having 1 to 10 carbon atoms such as -butyl, pentyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, neohexyl, heptyl, octyl, nonyl or decyl, or Formula R ^10- (Alk)-group (in the formula, Al
k is methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, A straight-chain or branched-chain carbon atom such as a group having 1 to 10 carbon atoms
Wherein R ¹⁰ is a carboxy group, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, hydroxyethoxycarbonyl or methoxyethoxycarbonyl, and is optionally substituted with a hydroxyl group or a lower alkoxy group having 2 to 5 carbon atoms. Alkoxycarbonyl group, carbamoyl group, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-
A mono- or dialkyl-substituted carbamoyl group such as dimethylcarbamoyl or N, N-diethylcarbamoyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl or 4-methyl-1-piperazinyl, 4-phenyl-1-piperazinyl, 5- or 6-membered cyclic aminocarbonyl group optionally having a substituent such as 4-acetyl-1-piperazinyl, a hydroxyl group,
A straight-chain or branched C1-C5 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or benzyloxy, and acetoxy, propionyloxy, butyryloxy, isobutyryloxy or pivaloyloxy. An aliphatic acyloxy group having 2 to 5 carbon atoms, benzoyloxy, p-toluoyloxy, o-anisoyloxy, 3-fluorobenzoyloxy, 4-chlorobenzoyloxy, 4-aminobenzoyloxy or 4
-Indicates an aromatic acyloxy group such as dimethylaminobenzoyloxy. ) Is given.

When R ³ represents an acyl group, R ³ is formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, acryloyl, methacryloyl,
Crotonoyl, octanoyl, decanoyl, tridecanoyl, pentadecanoyl, hexadecanoyl, octadecanoyl, nonadecanoyl, 2,6,10,14-tetramethylpentadecanoyl, eicosanoyl, 3-carboxypropanoyl, 4-carboxybutanoyl, 5-
Carboxypentanoyl, 7-carboxyheptanoyl, 3-ethoxycarbonylpropanoyl, 3-phenoxycarbonylpropanoyl, 3- (4-methylphenoxycarbonyl) propanoyl, 3- (4-methoxyphenoxycarbonyl) propanoyl, 3- (3 -Fluorophenoxycarbonyl) propanoyl, cis-3-
An aliphatic acyl group having 1 to 23 carbon atoms which may have an unsaturated bond such as carboxypropenoyl and trans-3-carboxypropenoyl (the acyl group is a carboxy group, a lower alkoxycarbonyl group or a substituted group). Optionally substituted with an aryloxycarbonyl group), cyclopentanecarbonyl, cyclohexanecarbonyl, cycloaliphatic acyl group such as cycloheptanecarbonyl, benzoyl, p-toluoyl, 3-nitrobenzoyl, 3-fluorobenzoyl. , 2-chlorobenzoyl, 4-aminobenzoyl, 3-dimethylaminobenzoyl, 2-methoxybenzoyl, 3,4-dichlorobenzoyl, 3,5-di-t-butyl-4-hydroxybenzoyl, 1-naphthoyl. Aromatic acyl group, 2-
Furoyl, 3-thenoyl, 3-pyridinecarbonyl, 4
Heterocyclic acyl group such as pyridinecarbonyl, araliphatic which may have a substituent such as phenylacetyl, 4-chlorophenylacetyl, 3-phenylpropionyl, cinnamoyl, and may have an unsaturated bond. Acyl group, lower alkoxy or aralkyloxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, or carbamoyl,
Examples thereof include substituted or unsubstituted carbamoyl groups such as N, N-dimethylcarbamoyl, N, N-diphenylcarbamoyl and N-benzyl-N-propylcarbamoyl.

When R ³ ′ represents an acyl group, R ³ ′ is an aliphatic acyl group having 2 to 4 carbon atoms such as acetyl, propionyl, butyryl, isobutyryl or benzoyl, p
- toluoyl, 4-nitro but aromatic acyl group such as benzoyl and the like, methanesulfonyl as R 3 ^', benzenesulfonyl, may indicate a sulfonyl group such as p- toluenesulfonyl.

When R ⁴ represents an alkyl group, R ⁴ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t
-Butyl, pentyl, isopentyl, neopentyl, t
-Pentyl, hexyl, 1,1-dimethylbutyl, 1,
3-dimethylbutyl, heptyl, 1,1-diethylpropyl, octyl, 1-methylheptyl, 2-ethylhexyl, 1,1,3,3-tetramethylbutyl, nonyl,
Examples thereof include linear or branched ones having 1 to 20 carbon atoms such as decyl, 3,7-dimethyloctyl, undecyl, dodecyl, pentadecyl, and eicosyl.

When R ⁴ represents an optionally substituted aralkyl group having 7 to 10 carbon atoms, R ⁴ is benzyl, 1-phenylethyl, 1-methyl-1-phenylethyl, 1-
Methyl-1- (4-methylphenyl) ethyl, 2-phenylethyl, 2- (3-methoxyphenyl) -1,1-
Examples thereof include dimethylethyl, 3- (2-chlorophenyl) propyl, 4-phenylbutyl and the like.

When R ⁴ is showing a cycloalkyl group which has carbon atoms that may 5 to 8 have a substituent, cyclopentyl as R ^4,
Examples thereof include cyclohexyl, 1-methylcyclohexyl, 2-methylcyclohexyl, 1-ethylcyclohexyl, 1-propylcyclohexyl, 1-isobutylcyclohexyl, cycloheptyl, 1-methylcycloheptyl, cyclooctyl and the like.

When R ⁴ represents an aryl group which may have a substituent, R ⁴
Examples of ⁴ include phenyl, 4-methylphenyl, 3-methoxyphenyl, 2-chlorophenyl and 2,4-dimethylphenyl.

When R ⁴ represents an alkoxy group, R ⁴ is methoxy,
Examples thereof include linear or branched ones having 1 to 12 carbon atoms such as ethoxy, propoxy, isopropoxy, butoxy, octyloxy, and dodecyloxy.

If R ⁵ represents an alkyl group, as methyl R ^5, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, heptyl, octyl, decyl, dodecyl, pentadecyl, straight-chain or branched-as eicosyl An example is a branched chain having 1 to 20 carbon atoms.

When R ⁵ represents an alkoxy group, R ⁵ is methoxy,
Examples include ethoxy, propoxy, isopropoxy, butoxy, octyloxy, and dodecyloxy. Further, adjacent R ⁴ and R ⁵ may represent a lower alkylenedioxy group such as methylenedioxy or ethylenedioxy which are formed together;
⁴ and R ⁵ are taken together to represent an optionally substituted formula —CH═CH—CH═CH—, which may form a naphthalene ring together with the adjacent benzene ring. Examples thereof include lower alkyl groups such as methyl, ethyl and isopropyl, and lower alkoxy groups such as methoxy and ethoxy.

When R ⁶ and R ⁷ represent an alkyl group, R ⁶ and R
⁷ are the same or different and are linear or branched ones having 1 to 5 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and isopentyl.

When Ar represents a divalent aromatic ring group which may have a substituent, Ar may be a p-phenylene group, an o-phenylene group or a m-phenylene group, in which case the substituent R ^{11 of} Ar is
Is methyl, ethyl, propyl, isopropyl, butyl,
Or it may be a lower alkyl group such as pentyl, a lower alkoxy group such as methoxy, ethoxy, isopoxy, t-butoxy, or pentyloxy.

When Ar represents a divalent heteroaromatic ring group which may have a substituent, Ar may be a pyridine ring, a furan ring, a thiophene ring, or a pyrrole ring, and its bonding position is represented by the formula: When shown by the model of (In the above formula, Q represents an oxygen atom, a sulfur atom, or an imino group.) In that case, the substituent R ¹¹ of Ar is methyl, ethyl, isopropyl, t-butyl, or pentyl. And lower alkoxy groups such as methoxy, ethoxy, isopropoxy, t-butoxy, or pentyloxy.

W is a methylene group; a carbonyl group; formula> CH-O
R ³ ′ group (in the formula, R ³ ′ has the same meaning as described above); Formula> = NOV group [in the formula, V is a hydrogen atom or a substituent having the same meaning as R ³ described above] Optionally linear or branched alkyl group having 1 to 10 carbon atoms or benzyl, 4-methylbenzyl, 3-methoxybenzyl, 1-chlorobenzyl, 1-phenylethyl, 2-
Phenylethyl, 3- (2-chlorophenyl) propyl or 4-phenylbutyl, 1-naphthylmethyl, 2-
It represents an aralkyl group having 7 to 11 carbon atoms which may have a substituent such as naphthylmethyl. ] Or the formula >> = N
Examples thereof include an —OR ³ ′ _a group (in the formula, R ³ ′ _a has the same meaning as described above), and may form a double bond with U described later.

U usually represents a methylene group, but may also represent a double bond together with W. U further has W as a carbonyl group and a formula> = N
-OV group (In the formula, V has the same meaning as described above.)
Alternatively, when a formula> = N-OR ³ ′ _a group (in the formula, R ³ ′ _a has the same meaning as described above), a double bond may be shown together with R ¹ . U can also represent a single bond.

Y represents an oxygen atom or an imino group.

Z represents an oxygen atom or an imino group, but when W is a methylene group, it can also represent a sulfur atom.

The target compound represented by the general formula (I) of the present invention is
It can be converted into a pharmaceutically acceptable non-toxic salt according to a conventional method, and examples of such a salt include salts of alkali metals such as sodium and potassium or salts of alkaline earth metals such as calcium. it can.

When the target compound represented by the general formula (I) of the present invention has a basic group, it can be converted into a non-toxic salt as described above, for example, hydrochloride, sulfate, nitrate, phosphoric acid. Inorganic acid salts such as salts; acetates, succinates,
Maleate, fumarate, malate, glutamate, aspartate, paratoluenesulfonate,
An organic acid salt such as methanesulfonate can be mentioned.

Further, in the object compound represented by the above general formula (I) of the present invention, preferred compounds include R ¹ being a hydrogen atom or a linear or branched alkyl group having 1 to 20 carbon atoms, and further It is a chain or branched alkyl group having 1 to 12 carbon atoms, particularly a linear or branched alkyl group having 1 to 9 carbon atoms, provided that R ² is a hydrogen atom or a lower atom. R ³ and R ³ ′ described below are the same or different and each is a hydrogen atom, an aliphatic lower acyl group, an alicyclic acyl group, an aromatic acyl group which may have a substituent, or a hetero group acyl. Group, an aromatic aliphatic acyl group which may have a substituent, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group, and R ⁴
And R ⁵ are the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R ⁶ , R ⁷ , R ⁸
And R ⁹ represents a hydrogen atom, Ar represents a p-phenylene group, W represents a methylene group, a carbonyl group or a formula = CH.
-OR ^{3 '(R 3'} have the same meanings as defined above.)
Represents a group represented by, U represents a methylene group, n represents an integer of 1 to 3, Y represents an oxygen atom or an imino group, and Z represents an oxygen atom or sulfur when W represents a methylene group. It indicates an atom or an imino group, Z is an oxygen atom or an imino if a group W is represented by a carbonyl group, or a group of the formula ^{= CH-oR 3 '(R} 3' have the same meanings as defined above.) When it represents a group, R ¹ is a linear or branched alkyl group having 6 to 20 carbon atoms, or a linear or branched alkyl group having 6 to 12 carbon atoms, and particularly A chain alkyl group having 7 to 9 carbon atoms; R ² is a hydrogen atom or a lower alkyl group, further a hydrogen atom or a methyl or isopropyl group, especially a methyl group; R ³ is a hydrogen atom or a substituted May be linear or branched An alkyl group having 1 to 5 carbon atoms [as a substituent of the alkyl group, a carboxy group, a linear or branched alkoxycarbonyl group having 2 to 5 carbon atoms (wherein the alkyl group portion of the alkoxycarbonyl group is a hydroxyl group or a straight chain); (May be substituted with a chain- or branched-chain alkoxy group having 1 to 5 carbon atoms), a hydroxyl group, a linear or branched alkoxy group having 1 to 5 carbon atoms, or 2 to 5 carbon atoms Benzoyloxy optionally substituted with one aliphatic acyloxy group or alkyl having 1 to 5 carbons or alkoxy having 1 to 5 carbons. ] And a C 2-5 aliphatic acyl group or aromatic acyl group which may be substituted with a carboxyl group. More preferably, a hydrogen atom, a substituted carboxy group, and a carbon number of 2 to 5
Is an alkoxycarbonyl group, a hydroxyl group or an alkyl group having 1 to 5 carbon atoms having an alkoxy group having 1 to 5 carbon atoms, an acetyl group or a benzoyl group, and particularly preferably a hydrogen atom, carboxymethyl, 1-carboxyethyl
3-carboxypropyl, ethoxycarbonylmethyl,
t-butoxycarbonylmethyl, pentoxycarbonylmethyl or formula It is carboxy or an alkyl group having 1 to 3 carbon atoms having an alkoxycarbonyl of 2 to 5 carbon atoms as a substituent such as a group; R 3 ^'is a hydrogen atom, an acetyl group or a benzoyl group, particularly preferably hydrogen Is an atom;
R ⁴ is a linear or branched alkyl group having 1 to 12 carbon atoms, more preferably a linear or branched alkyl group having 1 to 9 carbon atoms, and particularly methyl. , Isopropyl, t-butyl, t-pentyl, 1,1
-Dimethylbutyl, 1,1-diethylpropyl or 1,1,3,3-tetramethylbutyl group, provided that R ¹ and R ² are the same or different and each represents a hydrogen atom or a lower alkyl group, and R ³ R ^3's described below are the same or different and each have a hydrogen atom, an aliphatic lower acyl group, an alicyclic acyl group, an optionally substituted aromatic acyl group, a heterocyclic acyl group, or a substituent. Optionally represents an aromatic aliphatic acyl group, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group, R ⁵ is a hydrogen atom,
A lower alkyl group or a lower alkoxy group, R ⁶ ,
R ⁷ , R ⁸ and R ⁹ represent a hydrogen atom, Ar represents a p-phenylene group, W represents a methylene group, a carbonyl group or the formula ═CH—OR ³ ′ (R ³ ′ has the same meaning as described above. Represents a group represented by the formula), U represents a methylene group, n represents an integer of 1 to 3, Y represents an oxygen atom or an imino group, and Z represents oxygen when W represents a methylene group. atom, a sulfur atom or an imino group, Z is oxygen in the case of the proximal W is represented by a carbonyl group, or a group of the formula ^{= CH-oR 3 '(R} 3' have the same meanings as defined above.) When it represents an atom or an imino group, R ⁴ is a linear or branched alkyl group having 6 to 12 carbon atoms, and more preferably a branched alkyl group having 6 to 12 carbon atoms. Yes, especially 1,1-dimethylbutyl, 1,1-diethylpropyl Or a 1,1,3,3-tetramethylbutyl group; R ⁵ is a hydrogen atom, a lower alkyl group, a hydrogen atom or a methyl group, and particularly a methyl group; R ⁶
And R ⁷ are each a hydrogen atom; R ⁸ and R ⁹
Preferred substituents are hydrogen atoms or substituted alkyl groups having the same meaning as R ³ , especially hydrogen atoms; Ar is p
-Phenylene group, o-phenylene group, m-phenylene group, or formula And a p-phenylene group, an m-phenylene group, or a formula And is a p-phenylene group; R ¹¹ is a lower alkyl group, especially a methyl group; W is a methylene group;
Carbonyl group, And in particular a methylene group, a carbonyl group or the formula> =
N-OH, more particularly a methylene group; U is a methylene group or a double bond together with R ¹ , especially a methylene group; n is 1, 2 or 3, more preferably 1 or 2, especially 1 There is a compound in which Y is an oxygen atom; Z is an oxygen atom or an imino group, particularly an oxygen atom.

Specific examples of the thiazolidine derivative (I) of the present invention include, for example, compounds having the following structural formulas (first
Table).

In the table below, Me- represents methyl substitution.

In addition, a compound having the following structural formula (second
Table).

In addition, a compound having the structural formula shown below (the third
Table).

Further, compounds having the structural formulas shown below (Tables 4 to 5) can be mentioned.

In the following table, TMB is 1,1,3,3-tetramethylbutyl group, 5,5-dMH is 5,5-dimethylhexyl group, 3,3-dMB is 3,3-dimethylbutyl group, 3,7-dMO is a 3,7-dimethyloctyl group,
7,7-dMO represents a 7,7-dimethyloctyl group.

Further, a compound having the following structural formula (Tables 6 to 12) is used as a starting compound of the compound having the general formula (I) of the present invention and R ⁹ as a compound other than a hydrogen atom.
Table). However, in Table 11 and Table 12, the compound in which R ⁹ represents a hydrogen atom is a compound having the general formula (I) of the present invention.

The thiazolidine derivative (I) of the present invention can be produced, for example, as follows. That is, the formula (I)
Wherein W is a methylene group or a carbonyl group, and Z is an imino group, the compound (III) has the general formula (II) It is obtained by reacting the compound represented by and thiourea.

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,
R ⁷ , Ar, n and Y have the same meanings as described above, R ⁸ ′ represents a hydrogen atom or an alkyl group, W ₁ represents a methylene group or a carbonyl group, A represents a cyano group, a carboxy group, for example, Alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, carbomoyl groups or formula-COOM groups (wherein M is a metal atom such as sodium, potassium, calcium or aluminum or ammonium). And the like, and X represents a halogen atom such as chlorine, bromine or iodine. Note that the compound
As shown below, tautomers may be considered for (III), but for convenience, these are simply represented as formula (III).

When Y is an oxygen atom When Y is an imino group, The reaction between compound (II) and thiourea is usually carried out in a solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol, butanol and ethylene glycol monomethyl ether, ethers such as tetrahydrofuran and dioxane, acetone, dimethyl sulfoxide, sulfolane and dimethylformamide. The molar ratio of the compound (II) and thiourea to be used is not particularly limited, or it is preferable to use thiourea which is slightly in excess of the equimolar amount to the compound (II). It is preferably 1 to 2 mol with respect to 1 mol of the compound (II). Reaction temperature,
The reaction conditions such as the reaction time vary depending on the starting materials used, the solvent, etc., but the reaction is usually carried out at the boiling point of the solvent or at 80 to 150 ° C. for 1 hour to 20 hours.

In the formula (I), the compound (IV) of the present invention, wherein W is a methylene group and a carbonyl group, and Y and Z are both oxygen atoms.
Is a compound (III) isolated or without isolation,
It can be produced by hydrolysis.

As shown below, the compound (IV) may have tautomers, but for convenience, these are simply represented by the formula (IV).

In the hydrolysis step, compound (III) is heated in a suitable solvent (eg, sulfolane, methanol, ethanol, ethylene glycol monomethyl ether) in the presence of water, an organic acid such as acetic acid, or a mineral acid such as sulfuric acid or hydrochloric acid. It is done by doing. The amount of the acid added is usually compound (II
I) 0.1 to 10 mol, preferably 0.2 per 1 mol
~ 3 mol, the amount of water or aqueous solvent added is the compound (II
It is usually a large excess over I). The reaction temperature is usually 50 to 100 ° C., and the heating time is usually several hours to about 20 hours. After this hydrolysis step, the compound
R ^{3 in} (IV) usually represents a hydrogen atom [(IV) in which R ³ is a hydrogen atom is particularly represented by (IV _H ). ], But the acyl group can be left by selecting the reaction conditions.

The thiazolidine derivative (IV) obtained in the step can be prepared by a conventional method from various alkali metal such as sodium and potassium; alkaline earth metal such as calcium; or trivalent metal such as ammonium. A salt can be formed with a metal; preferably an alkali metal such as sodium and potassium; an alkaline earth metal such as calcium; and more preferably, an alkali metal such as sodium and potassium.

Further, in the thiazolidine derivative having a phenolic hydroxyl group, a mono-salt or a di-salt can be formed, if necessary, for monovalent metals such as sodium and potassium.

When the thiazolidine derivative (IV) obtained in the step has a basic group, if desired, hydrochloride, sulfate,
Inorganic acid salts such as nitrates, phosphates; like acetates, succinates, maleates, fumarates, malates, glutamate, aspartates, paratoluenesulfonates, methanesulfonates Can lead to various organic acid salts.

(IV _H ) is an acylating agent such as an acid halide or an acid anhydride, or an organic acid such as an aromatic carboxylic acid or an aliphatic carboxylic acid, a mineral acid such as hydrochloric acid or sulfuric acid, or paratoluene sulfone. The target ester can be converted by using a dehydrating agent or a dehydrating catalyst composed of an organic acid such as an acid. The reaction is usually performed in a solvent.
As the solvent to be used, ethers such as ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene, aliphatic hydrocarbons such as hexane, cyclohexane and heptane, halogens such as dichloromethane and chloroform. Hydrocarbons, ketones such as acetone and methyl ethyl ketone, amides such as dimethylformamide and dimethylacetamide, organic bases such as pyridine and triethylamine,
Examples thereof include sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, and water. Compound
The ratio of (IV _H ) to the acylating agent is not particularly limited, but the compound
It is advisable to use a slight excess of equimolar amount of acylating agent with respect to (IV _H ). Preferably, relative to 1 mol of compound (IV _H ),
The acylating agent is 1 to 10 mol. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials used and the type of solvent used, but are usually 0 ° C. to 100 ° C., and are several minutes to about 20 hours.

In the formula (I), the compound (VI) in which W is a hydroxymethylene group and Z is an imino group is a compound represented by the general formula (V) and a reducing agent such as sodium borohydride and K-selectride. , Especially by reacting sodium borohydride.

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,
R ⁷ , R ⁸ ′, Ar, n and Y have the same meanings as described above. The compound (VI) may be a tautomer as shown below, but for convenience, these are simply represented by the formula
Represented as (VI).

When Y is an oxygen atom When Y is an imino group, The reaction between compound (V) and sodium borohydride is usually carried out in a solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol, butanol, and ethylene glycol monomethyl ether,
Examples include ethers such as tetrahydrofuran and dioxane. The molar ratio of the compound (V) and sodium borohydride used is not particularly limited, but it is preferable to use sodium borohydride in excess with respect to the compound (V). It is preferably 1 to 20 mol with respect to 1 mol of the compound (V). The reaction conditions such as the reaction temperature and the reaction time vary depending on the starting materials used, the solvent, etc., but usually the reaction is 0 to 1.
It is carried out at 00 ° C. for 1 hour to about 20 hours.

In formula (I), W is a hydroxymethylene group, and Y and Z
The compound (VIII) in which both are oxygen atoms can be obtained by reacting the compound represented by the general formula (VII) with a reducing agent such as sodium borohydride or K-selectride, particularly sodium borohydride.

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,
R ⁷ , R ⁸ ′, Ar, and n have the same meanings as described above. The compound (VIII) may be a tautomer as shown below, but for convenience, these are simply represented by the formula
Represented as (VIII).

The reaction between compound (VII) and sodium borohydride is usually carried out in a solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol, butanol, and ethylene glycol monomethyl ether,
Examples include ethers such as tetrahydrofuran and dioxane. The molar ratio of the compound (VII) to sodium borohydride used is not particularly limited, but it is preferable to use an excess of sodium borohydride with respect to the compound (VII). It is preferably 1 to 20 mol per 1 mol of the compound (VII). The reaction conditions such as the reaction temperature and the reaction time vary depending on the starting materials used, the solvent, etc., but usually the reaction is 0 to 1.
It is 1 hour to about 20 hours at 00 ° C.

Further, the compound (VI) can be converted into the desired acyl compound (IX) by reacting with an acylating agent such as an acid halide or an acid anhydride.

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,
R ⁷ , R ⁸ ′, Ar, n, and Y have the same meanings as described above, and R ³ ′ _a represents the definition of R ³ ′ described above excluding a hydrogen atom. The compound (IX) may be a tautomer as shown below, but for convenience, these are simply represented by the formula (IX).

When Y is an oxygen atom When Y is an imino group The reaction is usually performed in a solvent. Examples of the solvent used include ethers such as ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane, cyclohexane and heptane, dichloromethane and chloroform. Examples thereof include halogenated hydrocarbons, organic bases such as pyridine and triethylamine, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, and sulfonic acids such as sulfolane.

The ratio of the compound (VI) to the acylating agent is not particularly limited, but it is preferable to use the acylating agent in a slight excess of equimolar amount to the compound (VI). Preferably, relative to 1 mol of compound (VI),
The acylating agent is 1 to 10 mol. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials used and the type of solvent used, but they are generally 0 to 100 ° C. and several minutes to about 20 hours.

Further, the compound (VIII) can be converted into the desired acylated product (X) by reacting with an acylating agent such as an acid halide or an acid anhydride. In the above formula, R ¹ , R ² , R ³ , R ³ ′ _a , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , R ⁸ ′, Ar, and n have the same meanings as described above. The compound (X) may have tautomers as shown below, but for convenience, these are simply represented by the formula (X).

The reaction is usually performed in a solvent. Examples of the solvent used include ethers such as ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane, cyclohexane and heptane, dichloromethane and chloroform. Examples thereof include halogenated hydrocarbons, organic bases such as pyridine and triethylamine, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, and sulfonic acids such as sulfolane. The ratio of the compound (VIII) to the acylating agent is not particularly limited, but it is preferable to use a slightly excess equimolar amount of the acylating agent relative to the compound (VIII). The amount of the acylating agent is preferably 1 to 10 mol, based on 1 mol of the compound (VIII). The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials used and the type of solvent used, but they are generally 0 to 100 ° C. and several minutes to about 20 hours.

In formula (I), W and U form a carbon-carbon double bond, and Z
The compound (XI) in which is an imino group is represented by the general formula (VI) or (IX)
In from a compound represented by, respectively, water or R ³ '
It is obtained by eliminating _a OH (in the formula, R ³ ′ _a has the same meaning as described above).

In the above formula, R ¹ , R ² , R ³ , R ³ ′ _a , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , R ⁸ ′, Ar, n and Y have the same meanings as described above. The compound (XI) may be a tautomer as shown below, but for convenience, these are simply represented by the formula (XI).

When Y is an oxygen atom When Y is an imino group, From compound (VI) or (IX), water or R respectively
^The reaction for eliminating ³ ′ _a OH is usually carried out in the presence or absence of an acid catalyst in a solvent, but the reaction may be carried out in an acidic solvent without using an acid catalyst. Examples of the catalyst include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as acetic acid and paratoluenesulfonic acid. Examples of the solvent include ethers such as ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane, cyclohexane and heptane, dichloromethane and chloroform. Examples thereof include halogenated hydrocarbons, ketones such as acetone and methyl ethyl ketone, amides such as dimethylformamide and dimethylacetamide, water, and a mixed solvent of the above solvents.

Examples of the acidic solvent include organic acids such as acetic acid. The ratio of the compound (VI) or (IX) to the catalyst is not particularly limited, but is 0. 0 with respect to the compound (VI) or (IX).
1 mol% to 100 mol%, preferably 1 to 1
It is 0 mol%. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials used, the type of solvent, etc., but are usually 0 to 100 ° C., and are several minutes to about 20 hours.

In formula (I), W and U form a carbon-carbon double bond, and Y
The compound (XII) in which both and Z are oxygen atoms has the general formula (VIII)
Alternatively, it can be obtained by eliminating water or R ³ ′ _a OH (wherein R ³ ′ _a has the same meaning as described above) from the compound represented by (X).

In the above formula, R ¹ , R ² , R ³ , R ³ ′ _a , R ⁴ , R ⁵ ,
R ⁶ , R ⁷ , R ⁸ ′, Ar, and n have the same meanings as described above. The compound (XII) may be a tautomer as shown below, but for convenience, these are simply represented by the formula (XII).

The reaction for eliminating water or R ³ ′ _a OH from compound (VIII) or (X), respectively, is usually carried out in a solvent in the presence or absence of an acid catalyst, but an acid catalyst is used. Alternatively, the reaction may be carried out in an acidic solvent. As the catalyst, inorganic acids such as hydrochloric acid and sulfuric acid,
Organic acids such as acetic acid and paratoluenesulfonic acid can be mentioned. Examples of the solvent include ethers such as ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane, cyclohexane and heptane, dichloromethane and chloroform. Examples thereof include halogenated hydrocarbons, acetone, ketones such as methyl ethyl ketone, water, and a mixed solvent of the above solvents.

Examples of the acidic solvent include organic acids such as acetic acid. The ratio of the compound (VIII) or (X) to the acid catalyst is not particularly limited, but is 0.1 mol% to 100 mol% with respect to the compound (VIII) or (X), preferably 1 to It is 10 mol%. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials used, the type of solvent, etc., but are usually 0 to 100 ° C., and are several minutes to about 20 hours.

In formula (I), W and U form a carbon or carbon double bond, and Z
Compound (XII) in which is an oxygen atom can also be produced by hydrolyzing compound (XI) in which Z is an imino group.

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,
R ⁷ , R ⁸ ′, Ar, n and Y have the same meanings as described above.

In the hydrolysis step, compound (XI) is heated in an appropriate solvent (eg, sulfolane, methanol, ethanol, ethylene glycol monomethyl ether) in the presence of water, an organic acid such as acetic acid, or a mineral acid such as sulfuric acid or hydrochloric acid. It is done by doing. The amount of acid added is usually compound (XI)
0.1 to 10 mol, preferably 0.2 to 1 mol
The addition amount of 3 mol, water or an aqueous solvent is usually in a large excess with respect to the compound (XI). The reaction temperature is usually 50 to 10
The temperature is 0 ° C., and the heating time is usually several hours to about 20 hours. After the hydrolysis step, the compound (XI
R ^{3 in} I) usually represents a hydrogen atom [(XII) in which R ³ is a hydrogen atom is particularly represented by the formula (XII _H ). ], But the acyl group can be left by selecting the reaction conditions.

In the formula (I), a compound [IV, (W ₁ = CH ₂ )] in which W is a methylene group and Y and Z are both oxygen atoms is
And U form a carbon-carbon double bond, and Y and Z are both oxygen atoms. The compound (XIII) can be produced by hydrogenating. In the formula, R ¹ , R ² , R ³ , R ⁴ ,
R ⁵ , R ⁶ , R ⁷ , R ⁸ ′, Ar and n have the same meanings as described above.

A catalytic reduction method is used as the hydrogenation reaction. Examples of the catalyst used for catalytic reduction include palladium-carbon, Raney-nickel, platinum oxide and the like, but palladium-carbon is preferable. The hydrogen pressure is 1 atm to 100 atm, preferably 1 atm to 6 atm. Examples of the solvent include alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, organic acids such as acetic acid, amides such as dimethylformamide and dimethylacetamide, Water and mixtures of these are mentioned. The reaction temperature and reaction time will differ depending on the starting materials and solvent used, but will usually be from room temperature to 50 ° C., and from a few minutes to about 20 hours.

In formula (I), compound (XV) in which W represents a carbonyl group, U represents a double bond together with R ¹ and Y and Z are both oxygen atoms is a compound represented by general formula (XIII) and a thiol group. It is produced via a compound represented by the general formula (XIV) obtained from urea. In formulas (XIII), (XIV), or (XV), ^{R 2, R 3, R 4} , R 5, R 6, R 7, R 8 ', A, A
r, n, X, Y, and Z have the same meanings as described above, L represents -OR ³ (R ³ has the same meaning as described above), or a double bond together with U, U is L
Is -OR ³ (R ³ has the same meaning as described above), it represents a methylene group. The thiazolidine derivative represented by the formula (XIV) and the formula (XV) may be a tautomer as previously shown in the formula (III) and the formula (IV),
For convenience, the isomers may also be represented by formula (XIV) and formula (X
V).

The reaction conditions and the like for obtaining compounds (XIII) to (XIV) and then (XV) are the same as the reaction conditions and the like for obtaining compounds (II) to (III) and then (IV).

In the formula (I), W is a formula> = N-OV (wherein V has the same meaning as described above), and in the compound (XVI) in which Z is an imino group, W is a carbonyl group. General formula (V ′) shown
The compound represented by the formula ( ₂ ) is reacted with a compound having the general formula H ₂ N-OV (the compound may be a salt of a mineral acid such as hydrochloric acid or sulfuric acid, and V has the same meaning as described above). It is obtained by

In the above formulas (V ′) and (XVI), R ¹ , R ² , R ³ , R
⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ′, Ar, n, U, V and Y have the same meanings as described above. Compound (XVI)
For example, tautomers may be considered as shown below, but for convenience, these are simply represented as formula (XVI).

When Y is an oxygen atom, When Y is an imino group, The reaction between the compound (V ′) and the compound: H ₂ NOV (the compound may be the salt described above, and V has the same meaning as described above) is usually sodium hydroxide, potassium hydroxide. Compound in the presence or absence of a deoxidizing agent represented by an alkali metal hydroxide or an alkali metal carbonate such as sodium carbonate or potassium carbonate: H ₂
It is achieved by reacting hydroxylamine derivatives represented by NOV (the compound may be the salt described above, and V has the same meaning as described above).

The reaction between the compound (V ′) and the compound having the formula H ₂ NOV is usually performed in a solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol, butanol and ethylene glycol monomethyl ether, ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide and dimethylacetamide, and dimethylsulfoxide. Examples thereof include sulfoxides, sulfones such as sulfolane, organic bases such as triethylamine and pyridine, or water, or a mixed solvent thereof.

In the reaction of the compound (V ′) with the hydroxylamine derivative represented by the formula H ₂ NOV, the molar ratio used is
Although not particularly limited, the compound (V ′) may be represented by the formula H ₂ N
The compound having OV may be in a large excess over equimolar amount, preferably 1 to 50 mol of the compound having the formula H ₂ NOV per 1 mol of compound (V ′). When the compound having the formula H ₂ NOV represents an inorganic acid salt of a hydroxylamine derivative, a deoxidizing agent may be used in the reaction, and a molar ratio of the deoxidizing agent to the inorganic acid salt is used. May be equimolar or less.

The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials used, solvent, etc., but are usually 0 to 100 ° C.
It takes a few minutes to about 10 days.

In particular, in the formula (I), W is the formula> = N-OV (wherein V has the same meaning as described above), and the compound (XVII) in which both Y and Z are oxygen atoms is to but compounds represented by the general formula (VII ') indicating a carbonyl group, the general formula H ₂ N
It can be obtained by reacting a compound having —OV (the compound may be a salt of a mineral acid such as hydrochloric acid or sulfuric acid, and V has the same meaning as described above).

In the above formulas (VII ′) and (XVII), R ¹ , R ² , R ³ , R
⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ′, Ar, n, U, and V have the same meanings as described above. The compound (XVII) may have tautomers, for example, as shown below, but for convenience, these are simply represented as the formula (XVII).

The reaction between the compound (VII ′) and the compound having the formula H ₂ NOV (wherein the compound may be the above-mentioned salt, V has the same meaning as described above), the reaction is usually sodium hydroxide,
Formula H _{2 in the} presence or absence of a deoxidizing agent represented by an alkali metal hydroxide such as potassium hydroxide or an alkali metal carbonate such as sodium carbonate or potassium carbonate.
This is achieved by reacting hydroxylamine derivatives represented by a compound having NOV (the compound may be the salt described above, and V has the same meaning as described above).

The reaction between the compound (VII ′) and the compound having the formula H ₂ NOV is usually performed in a solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol, butanol and ethylene glycol monomethyl ether, ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide and dimethylacetamide, and dimethylsulfoxide. Examples thereof include sulfoxides, sulfonic acids such as sulfolane, organic bases such as triethylamine and pyridine, water, and mixed solvents thereof.

In the reaction of the compound (VII ′) with the hydroxylamine derivative represented by the compound having the formula H ₂ NOV, the molar ratio used is not particularly limited, but the compound (VII ′) has the formula H ₂ NOV. The compound may be in a large excess over an equimolar amount, preferably 1 to 50 mol of the compound having the formula H ₂ NOV per 1 mol of the compound (VII ′). When the compound having the formula H ₂ NOV represents inorganic acid salts of hydroxylamine derivatives, a deoxidizing agent may be used in the reaction, and the molar ratio of the deoxidizing agent to the compound (VII ′) is deoxidizing. The agent may be equimolar or less. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials, solvent and the like used, but are usually 0 to 100 ° C. and several minutes to about 10 days.

In formula (I), W has the ^{formula> = N-O-R 3} 'a ( wherein,
R ³ ′ _a has the same meaning as described above. ) And Z
The compound (XX) in which is an imino group is obtained by reacting the compound (XVIII) in which V is a hydrogen atom in the above general formula (XVI) with an acylating agent such as an acid halide or an acid anhydride. can get.

In the above formula (XVIII) or (XX), R ¹ , R ² , R ³ ,
R ³ ′ _a , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ′, Ar,
U, n, and Y have the same meaning as described above. The compound (XX) may be a tautomer, for example, as shown below, but for convenience, these are simply represented by the formula (XX).

When Y is an oxygen atom, When Y is an imino group, The reaction between compound (XVIII) and the acylating agent is usually performed in a solvent. The solvent used is ether,
Ethers such as tetrahydrofuran, dioxane,
Aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane, cyclohexane and heptane, halogenated hydrocarbons such as dichloromethane and chloroform, organic bases such as pyridine and triethylamine, Examples thereof include amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane and water, or a mixed solvent thereof. The ratio of the compound (XVIII) to the acylating agent is not particularly limited, but it is preferable to use an excess of the acylating agent with respect to the compound (XVIII) in an equimolar amount, preferably 1 mol of the compound (XVIII). The acylating agent is 1 to 10 mol. Reaction temperature,
The reaction conditions such as the reaction time will differ depending on the starting materials used, the type of solvent used, etc., but are usually 0 ° C. to 100 ° C. and several minutes to about 20 hours.

Especially In formula (I), W has the ^{formula> = N-O-R 3} 'a ( wherein,
R ³ ′ _a has the same meaning as described above. ) And Y
The compound (XXI) in which both Z and Z are oxygen atoms is a compound (XI) in which V is a hydrogen atom,
It is obtained by reacting X) with an acylating agent such as an acid halide or an acid anhydride.

In the above formulas (XIX) and (XXI), R ¹ , R ² , R ³ and R ³ '
_{^{a, R 4, R 5,}} R 6, R 7, R 8 ', Ar, U, and n have the same meanings as defined above. Compound (XXI)
For example, tautomers may be considered as shown below, but for convenience, these are simply represented as formula (XXI).

The reaction between compound (XIX) and the acylating agent is usually performed in a solvent. Examples of the solvent used include ethers such as ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane, cyclohexane and heptane, dichloromethane and chloroform. Halogenated hydrocarbons such as, pyridine, organic bases such as triethylamine, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, sulfones such as sulfolane and water, or a mixture thereof. A solvent can be used. The ratio of the compound (XIX) to the acylating agent is not particularly limited, but it is preferable to use an excess of the acylating agent with respect to the compound (XIX) in an equimolar amount, preferably 1 mol of the compound (XIX). On the other hand, the acylating agent is 1 to 10 mol. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials used, the type of solvent used, etc., but are usually 0 ° C. to 100 ° C. and several minutes to about 20 hours.

Particularly, in the formula (I), W is a methylene group or a carbonyl group, U is a methylene group, and at least one of R ³ , R ⁸ and R ⁹ is an alkyl group which may be substituted, especially the above-mentioned substitutions. A compound which is an alkyl group and in which both Y and Z are oxygen atoms can be produced by the following three steps.

The first step is a step of producing a compound in which at least one of R ³ , R ⁸ and R ⁹ is an alkyl group which may be substituted with the aforementioned alkoxycarbonyl group or acyloxy group.

The reaction of this step is a compound (IV ′ _H ) in which R ³ , R ⁸ and R ⁹ are all hydrogen atoms. (In the formula, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Ar,
W ₁ and n have the same meanings as described above. ) Is preferably an alkyl halide in the presence of a base [wherein the alkyl group may be substituted with an alkoxycarbonyl group or an acyloxy group as described above, and the halide is preferably bromide. ] It is achieved by reacting with. After completion of the reaction, the desired compound can be obtained by separating the products by a conventional method such as column chromatography or preparative thin layer chromatography.

The reaction in this step is usually performed in a solvent. Examples of the solvent include ethers such as ethyl ether, tetrahydrofuran and dioxane, aliphatic hydrocarbons such as hexane, heptane and cyclohexane, aromatic hydrocarbons such as benzene, toluene and xylene, halogens such as methylene chloride and chloroform. Hydrocarbons, alcohols such as methanol, ethanol and tert-butanol, ketones such as acetone and methyl ethyl ketone, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, Examples thereof include organic acid groups such as pyridine and triethylamine, water, and mixed solvents of these solvents.

Examples of the base used include alkali metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate, sodium hydroxide,
Alkali metal hydroxide or alkaline earth metal such as potassium hydroxide or calcium hydroxide, sodium hydroxide,
Alkali metal hydrides such as potassium hydride, sodium methoxide, sodium ethoxide, potassium tert.
-Alkali metal alkoxides such as butoxy, organolithium compounds such as butyllithium, tert-butyllithium, lithium dialkylamides such as lithium diisopropylamide, lithium dicyclohexylamide,
Organic bases such as pyridine and triethylamine may be mentioned, but alkali metal carbonates such as potassium carbonate are preferred.

Ratio of the starting compound (IV _'H) alkyl halide starting compound per mol, an alkyl halide to 10 mol of the starting compound and the ratio of the base to the starting compound per mol, is a base 10 moles . The reaction conditions such as reaction temperature and reaction time will differ depending on the raw materials used, the alkyl halide, and the type of solvent used, but they are usually 10 to 100 ° C. and several minutes to several days.

In the reaction of this step, an alkyl group is introduced into R ⁸ and / or R ⁹ by using a compound in which the 6-position phenolic hydroxyl group is protected with a protecting group such as an acyl group, and the reaction product is used in a conventional method. The protecting group can be removed according to to obtain the desired compound.

The second step is an optional reaction,
It is a step of producing a compound in which at least one of R ³ , R ⁸ and R ⁹ is an alkyl group substituted with the above-mentioned carboxy group or hydroxyl group.

The reaction of this step is carried out by R ³ , R ⁸ obtained in the first step
And a compound in which at least one of R ⁹ is an alkyl group substituted with a corresponding alkoxycarbonyl group or acyloxy group is subjected to, for example, an acidic or basic hydrolysis reaction or an acidic olefin elimination reaction, preferably an acidic hydrolysis reaction or It is achieved by subjecting to an acidic olefin elimination reaction.

The reaction conditions for the acidic hydrolysis reaction are the same as the conventional methods, for example, the hydrolysis reaction conditions for the ester of the 6-position phenolic hydroxyl group or the imino group at the 2-position of the thiazolidine ring described in JP-A-58-158375.

The reaction conditions for the basic hydrolysis reaction are the same as the conventional methods, for example, the hydrolysis and solvolysis reaction conditions for the α-halogenocarboxylic acids shown in the above-mentioned publication.

The acidic olefin elimination reaction is preferably carried out when the alkoxycarbonyl group is a tert-butoxycarbonyl group, but is achieved in the presence of an inorganic or organic acid.

The reaction of this step is carried out in an organic solvent under anhydrous conditions according to a conventional method. The solvent used is the same as that mentioned in the first step, but ethers such as dioxane are preferable.

Examples of the acid used include mineral acids such as hydrochloric acid, sulfuric acid and phosphoric acid, organic acids such as acetic acid and trifluoroacetic acid, and sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid. Is a mineral acid such as hydrochloric acid. The reaction conditions such as reaction temperature and reaction time are usually 0 to 100 ° C. and several minutes to 24 hours.

The third step is a reaction that is carried out as desired,
It is a step of producing a compound in which at least one of R ³ , R ⁸ and R ⁹ is an alkyl group substituted with the aforementioned alkoxycarbonyl group or acyloxy group.

The reaction of this step is the reaction of R ³ and R ⁸ obtained in the second step.
And a compound in which at least one of R ⁹ is an alkyl group substituted with a corresponding carboxy group or a hydroxyl group is treated according to the usual conditions of an esterification reaction.

In the formula (I), W is a methylene group or a carbonyl group, U is a methylene group, R ³ and R ⁸ are hydrogen atoms, and R ⁹ is an optionally substituted alkyl group described above, compound Y and Z are both oxygen atoms may be obtained by selective alkylation of the compound described above (IV _'H). The reaction conditions of this reaction are the above-mentioned alkylation reaction, wherein the ratio of the starting compound to the alkyl halide is 1 to 1 mol of the starting compound, and
It is 5 mol, preferably 1 to 3 mol, and the reaction temperature and reaction time are 0 to 100 ° C. and 30 minutes to 3 hours.

In formula (I), W is a methylene group or a carbonyl group, U is a methylene group, Y and Z are both oxygen atoms, (a) R ⁸ is a hydrogen atom, and R ³ and R ^{9 are}
Is a substituted alkyl group (dialkyl substituted product) described above, or (b) R ³ , R ⁸ and R ⁹ is an optionally substituted alkyl group (trialkyl substituted product). it can be obtained by selective alkylation of the compound described above (IV _'H). The reaction conditions of this reaction are, in the above-mentioned alkylation reaction, the ratio of the raw material compound to the alkyl halide is 3 to 6 moles of the alkyl halide to 1 mole of the raw material compound, the reaction temperature and the reaction time are 15 to 40 ° C. 5 hours to 2 days. The reaction product can be further purified using a separation method such as chromatography.

In formula (I), W is a methylene group or a carbonyl group, U is a methylene group, R ³ and R ⁹ are hydrogen atoms, and R ³ is R ³ ′ _b [wherein R ³ ′ _b is A hydrogen atom and an acyl group are excluded from the definition of R ³ , and an optionally substituted alkyl group has an alkoxycarbonyl group or an acyloxy group which has the same meaning as described above. And a compound (IV _a ) in which both Y and Z are oxygen atoms is prepared by reacting the corresponding halogenocarboxylic acid derivative (II _a ) with thiourea, and then subjecting it to a hydrolysis reaction. Obtained by

In the above formula, R ¹ , R ² , R ³ ′ _b , R ⁴ , R ⁵ , R ⁶ ,
R ⁷ , Ar, W ₁ , n, A and X have the same meanings as described above.

The reaction of this step is carried out in the same manner as the reaction of the above-mentioned compound (II) with thiourea and then the hydrolysis reaction of the obtained 2-imino compound (III), but in the hydrolysis reaction of the imino group, When the solvent used is an alcohol, when the substituent R ³ ′ _b has an ester residue, transesterification with the solvent alcohol may occur, for example, when 2-methoxyethanol is used, Compound (I
R ³ ′ _b of V _a ) may represent a 2-methoxyethoxycarbonylalkyl group.

The compound (IV _a ) can be converted into _a compound in which the substituent R ³ ′ _b is an alkyl group substituted with a carboxy group or a hydroxyl group by the above-mentioned second step.

The starting compound (II _a ) in this production method is, for example, a compound corresponding to the compound (II) (W:> CH ₂ ) of the method A or the compound (II) (W:> = O) of the method D described later. The compound (3 ′) or (12 ′) can be produced according to the following alkylation reaction and can be obtained according to the method A or the method D below.

That is, chromanes (3H) represented by 6-hydroxy-2- (4-nitrophenoxyalkyl) chroman.
Alternatively, (12H) is reacted with an optionally substituted alkyl halide such as alkoxycarbonylmethyl halide as an optionally substituted alkyl halide such as methoxymethyl halide in the step A-2 described later. Thereby, the production of the starting material (3 ') or (12') in the present invention is achieved.

In the above formula, R ¹ , R ² , R ³ ′ _b , R ⁴ , R ⁵ , Ar,
W ₁ , n and X have the same meanings as described above.

The reaction of this step is the same as the reaction conditions of the alkylation reaction described above.

In formula (I), W is a hydroxymethylene group, and Y and Z
Are oxygen atoms and at least one of R ³ , R ⁸ and R ⁹ is an optionally substituted alkyl group, and the compound obtained by the above alkylation reaction is a carbonyl group. It can be obtained by reduction. The reaction conditions are the same as in the production of compound (VIII) by reduction of compound (VII) described above.

In formula (I), W is> = a N-OV group, Y and Z are both oxygen ^atoms, is R 3, ^{R 8} and at least one is an optionally substituted alkyl group ^{R 9} compound (wherein, V is. showing the same meanings as defined above) above alkylation W obtained by the reaction is a carbonyl group the compounds of formula H _{2 N-OV} is reacted with a hydroxylamine derivative having a Can be obtained by The reaction conditions compounds described above and (VII ') H ₂ N-
Similar to reaction with OV.

In formula (I), W is a> = NOR ³ ′ _a group, Y and Z are both oxygen atoms, and at least one of R ³ , R ⁸ and R ⁹ is an optionally substituted alkyl group. A certain compound can be obtained by acylating a compound, in which W is> = N-OH group, obtained by the above-mentioned oximation reaction, according to a conventional method. The reaction conditions are the same as those for the production of compound (XX) by acylation of compound (XVIII) described above.

In the formula (I), W is a> = CH-OR ³ ′ _a group, Y and Z are oxygen atoms, and R ³ , R ⁸ and R ^{9 are}
The compound in which at least one of the above is an optionally substituted alkyl group can be obtained by acylating the compound in which W is a hydroxymethylene group obtained by the above-mentioned reduction reaction, according to a conventional method. The reaction conditions are the same as in the production of compound (X) by acylation of compound (VIII) described above.

In formula (I), W and U form a carbon-carbon double bond, and Y
And Z are both oxygen atoms, and R ³ , R ⁸ and R
^The compound in which at least one of ⁹ is an optionally substituted alkyl group is water or R ³ from a compound in which W obtained by the above reaction is a hydroxymethylene group or a> CH—OR ³ ′ _a group. the 'a _OH can be obtained by desorption. The reaction conditions are the dehydration reaction of compound (VII) or R of compound (X) described above.
^{3 'is} similar to the preparation of the compounds according to the elimination reaction of a _OH (XII).

The corresponding compound in which W is a methylene group can be obtained by hydrogenating the compound having a carbon-carbon double bond formed by W and U obtained by the reaction of this step. The reaction conditions are the same as in the production of compound (IV) by hydrogenation of compound (XII) described above.

In formula (I), W represents a carbonyl group, U represents a double bond together with R ¹ , Y and Z are both oxygen atoms, and R
⁸ and R ⁹ are hydrogen atoms, R ³ is R ³ ′ _b ,
The compound (XV _a ) in which both Y and Z are oxygen atoms can be obtained by reacting the corresponding halogenocarboxylic acid derivative (XIII _a ) with thiourea and then hydrolyzing the reaction product. The starting compound of the present step (XIII _a) can be produced according to Process H described below, reaction with thiourea of the objective compound (XV _a) reaction conditions for producing the compound described above (XIII), followed It is similar to the production of compound (XV) by hydrolysis.

In formula (I), W represents a carbonyl group, U represents a double bond together with R ¹ , Y and Z are both oxygen atoms, and at least one of R ³ , R ⁸ and R ⁹ is substituted. The compound which may be an alkyl group is a compound (XV ′ _H ) in which R ³ , R ⁸ and R ⁹ are both hydrogen atoms. (In the formula, R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , Ar and n
Has the same meaning as described above. ) Is reacted with an alkyl halide in the presence of a base. The reaction conditions are the compound (X
The same as in the case of the alkylation reaction of _V'H ).

In formula (I), W is> = N-OV group or> = N-O
R ³ ′ _a group, U represents a double bond together with R ¹ ,
The compound in which Y and Z are both oxygen atoms and at least one of R ³ , R ⁸ and R ⁹ is a substituted alkyl group is more preferable than the compound obtained by the above reaction in which W is a carbonyl group. It can be obtained by the above-mentioned oxime formation reaction and its acylation reaction.

Using a compound having at least one of R ³ , R ⁸ and R ⁹ having an alkyl group substituted with a carboxy group or an alkoxycarbonyl group or a reactive derivative thereof obtained by the above-mentioned respective reactions, amidation according to a conventional method. By carrying out the reaction, a compound in which at least one of the substituents R ³ , R ⁸ and R ⁹ is an alkyl group substituted with a corresponding substituted or unsubstituted carbamoyl group can be obtained.

In Formula (I), (wherein, V is the same meanings as those described above.) W has the formula> = N-OV or formula> = ^N-OR 3 _'a
(Wherein R ³ ′ _a has the same meaning as described above), and the compounds belonging to the so-called oxime type, oxime ether type, and oxime ester type may be anti-type or syn-type. Of course, both isomers are included in the compound of the present invention.

The compound belonging to the oxime type can also be converted into a salt according to a conventional method. When the salt is a cation salt, the cation is an alkali metal ion such as sodium or potassium, or a calcium salt such as calcium. Examples thereof include alkaline earth metal ions and trivalent metal ions such as ammonium.

In the general formula (I), W is a methylene group, a carbonyl group, the formula> = N-OV group (wherein, V is the same meaning as above.) ^{Formula> = N-O-R 3} 'a group ( In the formula, R ³ ′ _a has the same meaning as described above.) Or when W forms a carbon-carbon double bond with U, in the thiazolidine derivative represented by the formula (I), at the 2-position of the chroman ring and thiazolidine. Each carbon atom at the 5-position of the ring is an asymmetric carbon atom, and isomers based on them are also included in the compound of the present invention.

Further, in the formula (I), W is a formula> CH—OR ³ ′ [R ³ ′ has the same meaning as described above. ], The formula (I)
In the thiazolidine derivative represented by, each of the carbon atoms at the 2-position and 4-position of the chroman ring and the 5-position of the thiazolidine ring is an asymmetric carbon atom, and isomers based thereon are also included in the compound of the present invention.

Further, in the formula (I), W is a carbonyl group, a formula = N—OV group, or a formula = N—O—R ³ ′ _a group (in the formula and R ³ ′ _a
Indicates the same meaning as described above. In the thiazolidine derivative in which U represents a double bond together with R ¹ , the carbon atom at the 5-position of thiazolidine is an asymmetric carbon atom, and isomers based thereon are also included in the compound of the present invention.

Thiazolidine derivative (I) obtained by the above reaction
Can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, recrystallization by crystallization, phase transfer, chromatography, and optical resolution method.

The α-halogenocarboxylic acid derivatives (II), which are the starting compounds for producing the target compound represented by the general formula (I) of the present invention, can be produced, for example, by the following method.

Method A Method A is already disclosed by the present inventors in Japanese Patent Application No. 58-158.
375 (abbreviated as the preceding item 1), which is equivalent to the method described in detail, and is advantageously used for producing a compound in which W is a methylene group in the general formula (II). In the general formula (II), a compound in which W ₁ is a methylene group is represented by (II) (W ₁ : CH ₂ ).

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,
R ⁷ , R ⁸ ′, Ar, n, X and A have the same meanings as described above, R ¹² represents a hydroxyl-protecting group, and m represents an integer of 0 to 9.

A-1 The A-1 step is a reduction step and is essentially the same as that shown in the above item 1.

A-2 The A-2 step is also essentially the same as shown in the previous item 1. Chroman alcohols obtained in step A-1 (2)
Are introduced into chromanes (3) having a nitro group in Ar (Ar has the same meaning as described above). It is preferable to protect the phenolic hydroxyl group prior to the reaction,
The hydroxyl-protecting group R ¹² is preferably an optionally substituted alkyl group such as methoxymethyl, 2-tetrahydropyranyl, methoxycarbonylmethyl, tert-butoxycarbonylmethyl and the like. Chroman alcohols having a protected phenolic hydroxyl group can be isolated without isolation, but without isolation
A compound having — (Ar) —NO ₂ (in the compound, Ar
And X have the same meaning as described above. ), Ar,
Lead to chromanes (3) having a nitro group.

A-3 The A-3 step is also essentially equivalent to that shown in the preceding item 1. The nitro compound (3) obtained in A-2 is reduced to the corresponding amino compound (4). In the reduction reaction, the protective group R ^{12 for} the phenolic hydroxyl group of the nitro compound (3) may be as it is, but may be deprotected, and another group,
For example, an acyl group such as an acetyl group or a benzoyl group may be used, and it is preferable to use an acyl group. When deprotecting compound (3), the deprotection step is (3)
Is hydrolyzed in the presence of a low concentration of acid. When the protecting group of the compound (3) is changed to an acyl group or the like, the acylation is performed by further adding the compound deprotected by the above hydrolysis to acid halides such as acetyl chloride and benzoyl chloride, and acid anhydrides such as acetic anhydride. It is achieved by treatment with an acylating agent of the class. The reduction reaction from the nitro form (3) to the amino form (4) includes catalytic reduction or reduction with a metal such as zinc or iron and an acid (for example, a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid). However, catalytic reduction is preferable.

A-4 The A-4 step is also essentially equivalent to that shown in the preceding item 1.

In step A-4, the chromane (4) having an amino group in Ar (Ar has the same meaning as described above) is diazotized, and then mainvine arylation (Meerwein
Arylation) is a raw material for the target compound (I) in the present invention. Production of α-halogenocarboxylic acid derivatives (II) (W: CH ₂ ) is achieved. The reaction is diazotized with nitrites such as sodium sulfite in the presence of hydrochloric acid, hydrobromic acid, etc., and then acrylic acid, methyl acrylate, acrylic acid esters such as ethyl acrylate, ethyl crotonate, methacrylic acid. Ethyl acid, acrylonitrile, methacrylonitrile, acrylic acid amide,
A general formula such as methacrylic acid amide R ⁶ R ⁷ C = CR ⁸ ′
An acrylic acid derivative represented by A (in the formula, R ⁶ , R ⁷ , R ⁸ and A have the same meanings as described above), or an acrylic acid homolog, (wherein R ⁶ or R ⁷ is Preferably a hydrogen atom; R ⁸ ′ preferably represents a hydrogen atom or a methyl group, particularly a hydrogen atom), and a catalytic amount of cuprous salts such as cuprous chloride and cuprous oxide is allowed to act on the catalyst. To start by. Acrylic acid derivatives are preferable as the acrylic acid derivative, and cuprous oxide is preferable as the cuprous salt. Examples of the solvent for the reaction include alcohols such as methanol and ethanol, acetone, ketones such as methyl ethyl ketone, water, and a mixture thereof. The ratio of the amino compound (4) and the acrylic acid derivative is 1 to 15 mol, preferably 5 to 5 mol, of the acrylic acid derivative with respect to 1 mol of the compound (4).
It is 10 mol. The ratio of the compound (4) to the cuprous salt is 0.01 to 1 mol, and preferably 0.03 to 0.3 mol, relative to 1 mol of the compound (4). The reaction temperature and the reaction time will differ depending on the starting materials, solvent and the like used, but are usually at room temperature to 100 ° C. for about 10 minutes to about 2
It is 0 hour, preferably 30 minutes to 2 hours at 40 to 60 ° C.

Method B Method B is also advantageously used to synthesize compounds of formula (II) where W is a methylene group.

Among the chroman alcohols (2), compounds in which n is 2, for example, are described in Journal of American Oil Chemistry Society Vol. 51 , p. 200 (19).
74) [J. Am. Oil Chemist's Soc., 51 , 200 (1974)], which can be produced from hydroquinones (5) in multiple steps. 2017
It is also possible to manufacture in one step according to the method shown in No. 75. In the above reaction formula, R ¹ R ² , R ³ , R ⁴ ,
And R ⁵ has the same meaning as described above. After that, A-2
According to the following method, by using a method over several steps, α-halogenocarboxylic acid derivatives (II) (W: C
The synthesis of H ₂ ) is achieved.

Method C Method C is also advantageously used to synthesize compounds where W and U are methylene groups in general formula (II).

This Act is the Journal of Medicinal Chemistry
18 , p. 934 (1975) [J. Med. Chem., 18 , 934 (197).
5)], and to introduce R ¹ ′ (R ¹ ′ is the definition of R ¹ excluding a hydrogen atom) at the 2-position of the chroman ring. , Can be advantageously used.

In the above formula, R ¹ ′, R ² , R ⁴ , R ⁵ , and R ¹² have the same meanings as described above, and B ₁ is a carboxylic acid protecting group such as an alkyl, alkenyl, alkynyl, aralkyl group, or a substituted group. The optionally substituted phenyl group is preferably a lower alkyl group, but may be a hydrogen atom if protection is not particularly required.

C-1 to C-4 Steps C-1 to C-4 are essentially the same as the method described in the above document.

C-5 The C-5 step is a step for protecting the phenolic hydroxyl group, which is carried out as necessary, but it is preferable to protect the phenolic hydroxyl group prior to the C-6 step. When protecting a hydroxyl group, as the protecting group R ¹² , a usual protecting group for a phenolic hydroxyl group, for example, an alkoxyalkyl group such as methoxymethyl, 2-tetrahydropyranyl, or an optionally substituted benzyl group, Examples thereof include acyl groups such as acetyl, acetyl and benzoyl, and alkoxyalkyl groups are preferable. The reaction for introducing a protecting group is usually carried out using an alkali or alkaline earth metal hydride such as sodium hydride, potassium hydride, calcium hydride, sodium methoxide, sodium ethoxide, and potassium tertiary butoxide. This can be achieved by using an alkoxyalkylating agent such as chloromethyl methyl ether or an alkylating agent such as benzyl halide in the presence of a base such as various alkali metal alcoholates. In the reaction, as the solvent, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane and heptane, dimethylformamide, Examples thereof include amides such as dimethylacetamide, sulfoxides such as dimethylsulfoxide, and sulfones such as sulfolane. Compound (9)
The ratio of the alkylating agent and the alkylating agent is not particularly limited,
It is advantageous to use a slight excess of the alkylating agent relative to (9). Preferably, with respect to 1 mol of compound (9),
The acylating agent is 1 to 2 mol. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials, solvent and the like used, but the reaction is usually carried out at 0 to 50 ° C., preferably 10 to 25 ° C. for several minutes to several hours. The chromancarboxylic acid derivatives protected in this manner can be isolated, but can be used for the alkylation reaction at the 2-position of the chroman ring in the C-6 step without isolation.

Step C-6 The step C-6 is a step of producing a chromancarboxylic acid derivative (11) having a protected hydroxyl group at the 6-position of the chroman ring and R ¹ ′ at the 2-position of the same ring, if desired. 6
Chromancarboxylic acid having a protected hydroxyl group at position (1
0) is treated with a base in an inert solvent to generate a carbanion in the reaction solution, and then the compound of the general formula R ¹ ′ -X ′ (wherein R is
^{1 'represents} the same meaning as described above, X' is chlorine, bromine, halogen atom or a methanesulfonyloxy, such as iodine, ethanesulfonyloxy, benzenesulfonyloxy, the p- toluenesulfonyl sulfonyloxy groups such as oxy Show. Is achieved by reacting a compound having Examples of the base used include organic lithium compounds such as methyllithium, n-butyllithium, t-butyllithium and phenyllithium; lithium dialkylamides such as lithium diisopropylamide, lithium dicyclohexylamide and lithium isopropylcyclohexylamide. Examples thereof include alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride and the like, with preference given to organolithium compounds or lithium dialkylamides.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include ethers such as ether, tetrahydrofuran and dioxane.

The reaction temperature is −78 ° C. to room temperature for the generation of the anion in the ^first stage, and 0 ° C. to 60 ° C. for the reaction of the anion in the second stage with R ¹ ′ —X ′, and the time required for the reaction is 30 minutes in the first stage. To 2 hours, 1 hour to 24 hours in the latter stage
It's time.

After that, the α-halogenocarboxylic acid derivatives (II) (W: C
The production of H ₂ ) is achieved.

If desired, using a chromancarboxylic acid (10) in which R ¹ is a hydrogen atom, the reaction according to the step A-1 and the subsequent reactions are directly carried out without going through the step C-6. By doing so, production of α-halogenocarboxylic acid derivatives (II) (W: CH ₂ ) in which R ¹ is a hydrogen atom is achieved.

Method D The method D has already been described by the present inventors in JP-A-61-362.
This is equivalent to the method described in detail in No. 84 (abbreviated as No. 2 ₎ and is represented by a compound [(II) _{(W:> = 0) in} which W is a carbonyl group in the general formula (II). ] Is advantageously used to produce

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ ,
R ⁷ , R ⁸ ′, Ar, n, X and A have the same meanings as described above.

D-1 and D-2 The D-1 and D-2 steps are essentially the same as those shown in the previous item 2.

D-3 Step D-3 corresponds to Step A-4 described above and is achieved in the same manner as Step A-4.

Method E In the method E, W is a carbonyl group in the general formula (II), and a compound having a substituent R ¹ ′ (R ¹ ′ has the same meaning as described above) at the 2-position of the chroman ring is produced. Used to advantage.

In this method, the chromonecarboxylic acid (8) obtained in the previous step C-3 is treated under a milder condition than that used in the step C-4, and a double atom formed by the carbon atoms at the 2nd and 3rd positions is formed. Reducing only the bond (E-1); and E-2 to E
Each step of -7;

In the formula, R ¹ ′, R ² , R ⁴ , R ⁵ , R ¹² , Ar and B
₁ has the same meaning as described above, and B ₂ represents a protected carbonyl group. Each step will be described in detail below.

Step E-1 Step E-1 is a step of obtaining 4-oxochromancarboxylic acids (14) from chromonecarboxylic acids (8). Catalytic reduction is used as the reduction method. Examples of the catalyst used for catalytic reduction include palladium-carbon, Raney-nickel, platinum oxide and the like, but palladium-carbon is preferable.
It is carbon. The hydrogen pressure is 1 to 100 atm,
1 atm to 6 atm is preferred. As the solvent, alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, amides such as dimethylformamide and dimethylacetamide, organic acids such as acetic acid,
Water and mixtures of these are mentioned, with the amides being preferred. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials and solvent used, but are usually room temperature to 5
The temperature is 0 ° C., preferably room temperature to 40 ° C., and the time is several minutes to several days, preferably about 30 minutes to about 20 hours.

E-2 Step E-2 is for 4-oxochromancarboxylic acids (14)
The carbonyl group is optionally protected, but it is desirable to carry out the protection prior to the alkylation reaction at the 2-position of the chroman ring in the E-4 step. The protecting group is not particularly limited as long as it is a usual protecting group for a carbonyl group, and the oxo compound may be converted into, for example, a protected enol such as enol ethers or enol esters, It may be converted into a cyclic or acyclic ketone acetal ring or ketone dithioacetals, and conversion into ketone dithioacetals is preferable. Chroman carboxylic acid (15) wherein with a protected carbonyl ^{group, R 2, R 4, R} 5, and _{B 1} represents the same meaning as above, _{B 2} is the formula _-B 3 -B ₄ -
B ₃ −, B ₃ represents an oxygen atom or a sulfur atom, preferably a sulfur atom, and B ₄ represents, for example, the formula — (CH ₂ ).
₂ -, the formula - _{(CH 2) 3} -, the formula - _{(CH 2) 4} - or formula _{CH 2 -CH = CH-CH 2} - (cia), preferably of formula - (CH
_{2) 2} - or formula - _{(CH 2) 3} -, especially formula - (C
H ₂ ) ₃ −. ] The production of 4-oxochromancarboxylic acids (14), ethylene glycol,
1,3-propanediol, 1,2-propanedithiol, 1,3-propanedithiol or cis-2-
Such as butene-1,4-diol _{H-B 3 -B 4 -B 3} -H
(Wherein B ₃ and B ₄ have the same meanings as described above), preferably 1,3-propanedithiol by dehydration reaction in the presence or absence of a catalyst. . As the catalyst, boron trifluoride,
Its ether complex salt, its acetic acid complex salt, Lewis acids such as aluminum chloride; or inorganic acids such as hydrochloric acid and sulfuric acid; organic such as acetic acid, succinic acid, fumaric acid, maleic acid, paratoluenesulfonic acid, or methanesulfonic acid Examples of the acids include Lewis acids, particularly acetic acid complex salts of boron trifluoride. Although a solvent may not be used, when a solvent is used, aromatic hydrocarbons such as benzene and xylene, halogenated hydrocarbons such as chloroform and dichloromethane are preferably used as the solvent. Such halogenated hydrocarbons can be mentioned. Compound (14) and H-B ₃ -
B ₄ is not particularly limited proportion of the -B ₃ -H, the compound (1
Slight excess of H-B than equimolar to _{4) 3} -B 4 -B ₃ -H
Is better to use. Preferably compound (14) with respect to 1 mol of a compound 1 to 2 moles of the formula _{H-B 3 -B 4 -B 3} -H. The ratio of the compound (14) to the catalyst is not particularly limited, but it is 1 to 4 mol of the catalyst with respect to 1 mol of the compound (14). The reaction conditions such as reaction temperature and reaction time vary depending on the starting materials used and the type of solvent, but are generally 0
C. to 100.degree. C., preferably 10.degree. To 40.degree. C., several minutes to several days, preferably 1 hour to 30 hours.

E-3 Step E-3 is a step of protecting the phenolic hydroxyl group at the 6-position of the same ring of the chromancarboxylic acid (15) having a protected carbonyl group at the 4-position of the chroman ring, if necessary. It is preferable to carry out the protection prior to the alkylation reaction at the 2-position of the chroman ring in step E-4. As the hydroxyl-protecting group R ¹² , an ordinary phenolic hydroxyl-protecting group, for example, an optionally substituted alkyl group such as methoxymethyl, 2-tetrahydropyranyl, methoxycarbonylmethyl, t-butoxycarbonylmethyl, etc. Or, a benzyl group which may be substituted, an acetyl group, an acyl group such as benzoyl, and the like.
An alkoxyalkyl group or an alkoxycarbonylalkyl group is preferable. The reaction for introducing a protecting group is usually
Of alkali or alkaline earth metal hydrides such as sodium hydride, potassium hydride, calcium hydride, and bases such as alkali metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tertiary butoxide. In the presence of chloromethyl methyl ether, methyl bromoacetate, bromoacetic acid t
This is accomplished by using an alkylating agent such as butyl or an alkylating agent such as penzyl halide. In the reaction, as the solvent, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane, aliphatic hydrocarbons such as hexane and heptane, aromatic hydrocarbons such as benzene, toluene and xylene, dimethylformamide, Examples thereof include amides such as dimethylacetamide, sulfoxides such as dimethyl sulfoxide, and sulfones such as sulfolane. The ratio of the compound (15) to the alkylating agent is not particularly limited, but it is preferable to use the alkylating agent in a slight excess over equimolar amount to (15), and preferably (1
5) The alkylating agent is 1 to 2 mol per 1 mol. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials used, the solvent, etc., but usually 0 to 5 for the reaction.
It is carried out at 0 ° C. for several minutes to several hours. The chromancarboxylic acids (16) thus protected can be isolated, but can also be used in the E-4 step without isolation.

E-4 Step E-4 is a chromancarboxylic acid having a hydroxy group protected at the 6-position of the chroman ring, a carbonyl group protected at the 4-position of the same ring, and a chromancarboxylic acid having R ¹ ′ at the 2-position of the same ring (17 In the process of producing), a hydroxyl group protected at the 6-position of the chroman ring,
Chroman carboxylic acids (16) having a carbonyl group protected at the 4-position of the same ring are treated with a base in an inert solvent to generate a carbanion in the reaction solution, and then the compound of the general formula R ¹ ′-
X ′ (in the formula, R ¹ ′ has the same meaning as described above,
X'represents a halogen atom such as chlorine, bromine, iodine or a sulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy and p-toluenesulfonyloxy. Is achieved by reacting a compound having Examples of the base used include organic lithium compounds such as methyllithium, n-butyllithium, t-butyllithium and phenyllithium; lithium dialkylamides such as lithium diisopropylamide, lithium dicyclohexylamide, lithium isopropyl and cyclohexylamide. Amides; or alkalmetal hydrides such as lithium hydride, sodium hydride, potassium hydride and the like can be mentioned, but organolithium compounds or lithium dialkylamides are preferable.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include ethers such as ether, tetrahydrofuran and dioxane.

The reaction temperature is −78 ° C. to room temperature for the generation of the anion in the ^first stage, and 0 ° C. to 60 ° C. for the reaction of the anion in the second stage with R ¹ ′ —X ′, and the time required for the reaction is 30 minutes in the first stage. To 2 hours, 1 hour to 24 hours in the latter stage
It's time.

If desired, chromancarboxylic acids (16) in which R ¹ is a hydrogen atom are used, and the reduction reaction directly according to the E-5 step and each of the steps shown below are performed without passing through the E-4 step. By carrying out the reaction, α-halogenocarboxylic acid derivatives (II) _{(W:> = 0) in} which R ¹ is a hydrogen atom can be produced.

E-5 The E-5 step is performed by chroman-2-carboxylic acid (17).
To the corresponding alcohols (1
In the step of reducing to 8), examples of the reducing agent include lithium aluminate hydride and vitride (sodium bis [2-methoxyethoxy] aluminum).
Hydrides) are used. As the solvent used in the reduction reaction, for example, ethers such as diethyl ether, tetrahydrofuran, ethylene glycol dimethyl ether, benzene,
Examples thereof include aromatic hydrocarbons such as toluene and xylene, and aliphatic hydrocarbons such as hexane, hepetane, cyclohexane, petroleum ether, ligroin, and ethylcyclohexane.

The ratio of the compound (17) to the reducing agent is not particularly limited, but it is preferable to use a slightly excess reducing agent with respect to the compound (17). Preferably, 1 mol per 1 mol of compound (17)
~ 2 moles. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials used, solvent, etc., but are usually -5
The reaction is performed at 0 ° to 120 ° C. for about 10 minutes to about 20 hours.

E-6 Process E-6 is the alcohol (1) obtained in Process E-5.
8) is a step of introducing a formula (Ar) -NO ₂ group (in the formula, Ar has the same definition as described above). In this step, the compound (1
8) In general, bases such as alkali hydrides or alkaline earth metals such as sodium hydride and calcium hydride, and alkali metal alcoholates such as sodium methoxyside, sodium ethoxide and potassium tert-butoxide. Preferably, sodium hydride or sodium ethoxide is reacted to give compound (18) as a corresponding alkoxide, which has a compound of formula X- (Ar) -NO ₂ (wherein X, Ar
Has the same meaning as described above. ) Is achieved. In the reaction, as the solvent, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane and heptane, dimethylformamide, Examples thereof include amides such as dimethylacetamide, sulfoxides such as dimethyl sulfoxide, and sulfones such as sulfolane, and amides are preferably used. The ratio of the compound (18) to the base is not particularly limited, but it is preferable to use a slight excess of the base with respect to the compound (18), preferably 1 to 2 bases per 1 mol of the compound (18). It is a mole. The ratio of the compound (18) to the compound having the formula X- (Ar) -NO ₂ (wherein X and Ar have the same meanings as described above) is not particularly limited, but the ratio to the compound (18) is not limited. excess of formula X- (Ar) often use a compound having -NO _2, preferably (18) with respect to 1 mole, 1 to 10 mol. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials, solvent and the like used, but are usually 30 ° C. to 100 ° C. and several minutes to several hours.

The nitro compound (19) having a carbonyl group protected at the 4-position of the chroman ring, obtained in this step, undergoes a reduction reaction and a Mailbain arylation according to Method A to obtain α-halogenocarboxylic acid derivatives and further objects. The compound (I) is converted stepwise, and the deprotection reaction at the 4-position of the chroman ring may be carried out at any of the above steps. For example, as one of preferred methods, the step shown in E-7 is performed. I can give you.

E-7 Step E-7 is a step of deprotecting the nitro compound (19) having a hydroxyl group protected at the 6-position of the chroman ring and a carbonyl group protected at the 4-position, if desired. In this step, the deprotection reaction at the 4-position is usually carried out, but by setting a slightly more radical reaction condition, the deprotection at the 6-position can be achieved at the same time.

The deprotecting agent is not particularly limited, but a conventional deprotecting agent, for example, a protic acid such as hydrochloric acid or sulfuric acid; boron trifluoride, an ether complex salt thereof, an acetic acid complex salt thereof, a Lewis acid such as ammonium chloride; When B ₃ is a sulfur atom,
Examples thereof include heavy metal salts, heavy metal oxides or heavy metal peroxides; or a mixture of two or three of these, and the noble metal ions include silver, cadmium, divalent mercury, divalent copper, and trivalent thallium. Examples of the counter ion of the noble metal ion include halogen ions such as chlorine, bromine and iodine, peroxide ions such as nitrate ion and perchlorate ion, and other sulfuryl halides such as iodine and sulfuryl chloride. , N-halosimides such as N-chlorosuccinimide and N-bromosuccinimide are preferred, and mercuric chloride is preferred, or a mixture thereof, particularly a mixture thereof. Examples of the solvent used include alcohols such as methanol, ethanol, propanol and isopropanol, ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, ethers such as tetrahydrofuran and dioxane. And organic acids such as acetic acid, nitriles such as acetonitrile, and water, and mixed solvents thereof.

The ratio of the compound (19) to the deprotecting agent is not particularly limited,
Usually, 1 to 10 mol of the deprotecting agent per 1 mol of (19),
It is preferably 1 to 4 mol. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials and solvent used, but are usually room temperature to 100 ° C., preferably 40 to 8
At 0 ° C., it is several minutes to several hours, preferably 0.5 to 4 hours.

Thereafter, the α-halogenocarboxylic acid derivatives (II) are prepared by sequentially using a method according to the following method in step D-2.
Manufacturing of _{(W:> = 0)} is achieved.

Method F The method F is preferably used for producing a compound of the general formula (II) in which W is a methylene group from the compound (12) having a carbonyl group at the 4-position of the chroman ring described in the description of method D. used.

In the formula, R ¹ , R ² , R ³ , R ³ ′ _a , R ⁴ , R ⁵ , and A
r, n and (II) (W ₁ : CH ₂ ) have the same meaning as described above.

F-1 In the F-1 step, the 4-oxochroman compound (12) having a nitro group is converted into the corresponding 4-hydroxy compound (2
This is a step of reducing to 1). Examples of the reducing agent include reducing agents such as sodium borohydride and K-selectride, and sodium borohydride is particularly preferable.

The reaction between compound (12) and sodium borohydride is usually carried out in a solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol, butanol and ethylene glycol monomethyl ether, and ethers such as tetrahydrofuran and dioxane. The molar ratio of the compound (12) and sodium borohydride used is not particularly limited, but it is preferable to use an excess of sodium borohydride with respect to the compound (12). It is preferably 1 to 20 mol per 1 mol of the compound (12). The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials, solvent and the like used, but the reaction is usually at 0 ° C to 100 ° C for 1 hour to about 20 hours.

F-2 In the F-2 step, the hydroxy derivative (21) can be used, if desired.
Is a step of acylating. The compound (21) can be converted to the desired acyl compound (23) by reacting with an acylating agent such as an acid halide or an acid anhydride.

The reaction is usually performed in a solvent. Examples of the solvent used include ethers such as ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane, cyclohexane and heptane, dichloromethane and chloroform. Examples thereof include halogenated hydrocarbons, organic bases such as pyridine and triethylamine, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, and sulfones such as sulfolane.

The ratio of the compound (21) to the acylating agent is not particularly limited, but it is preferable to use a slightly excess equimolar amount of the acylating agent with respect to the compound (21). Preferably compound (21)
The amount of the acylating agent is 1 to 10 mol per 1 mol. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials used and the type of solvent used, but they are generally 0 to 100 ° C. and several minutes to about 20 hours.

F-3 The F-3 step is carried out by removing water from the 4-hydroxychroman compound (21) having a nitro group to give 2H.
-A step of producing chromenes (22).

The elimination reaction is accomplished in the presence or absence of a dehydrating agent or dehydrating catalyst. Examples of the dehydrating agent or dehydrating catalyst include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, organic acid salts such as acetic acid, succinic acid and maleic acid, paratoluenesulfonic acid, naphthalenesulfonic acid and methanesulfonic acid. Examples thereof include sulfonic acids, inorganic salts such as ammonium chloride and calcium chloride, phosphorus pentoxide, polyphosphoric acid, silica gel, alumina, and the like, and organic acids such as acetic acid and sulfonic acids such as paratoluenesulfonic acid are preferable.

A solvent may not be used in the elimination reaction, but when a solvent is used, alcohols such as methanol, ethanol and isopropanol, acetone and methyl are used.
Ketones such as ethyl ketone, ethers such as ether, tetrahydrofuran, dioxane, aromatic hydrocarbons such as benzene, toluene, xylene, aliphatic hydrocarbons such as hexane, cyclohexane and heptane, dichloromethane, chloroform. Organic acids such as halogenated hydrocarbons, acetic acid, propionic acid, etc.
Pyridine, organic bases such as triethylamine, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide,
Examples thereof include sulfones such as sulfolane, water and the like, and aromatic hydrocarbons such as benzene or organic acids such as acetic acid are preferable. When a dehydrating agent or a dehydrating catalyst is used, the ratio of the compound (21) to the dehydrating agent or the dehydrating catalyst is not particularly limited, but the dehydrating agent or the dehydrating catalyst is usually added to 1 mol of the compound (21). It is 0.01 to 10 mol, preferably 0.1 to 3 mol. The reaction conditions such as reaction temperature and reaction time will differ depending on the raw materials used and the type of solvent used, but are usually 0 to 100
C, several minutes to about 20 hours.

F-4 The F-4 step is performed by converting the 4-acyloxychroman compound (23) having a nitro group into the compound R ³ ′ _a OH (R ³ ′
_a has the same meaning as described above. Is a step of producing 2H-chromenes (22).

The elimination reaction is accomplished in the presence or absence of a deoxidizing agent or deoxidizing catalyst. Examples of the deoxidizer or dehydration catalyst include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, organic acids such as acetic acid, succinic acid and maleic acid, paratoluenesulfonic acid, naphthalenesulfonic acid and methanesulfonic acid. Examples thereof include sulfonic acids, inorganic salts such as ammonium chloride and calcium chloride, organic bases such as pyridine and triethylamine, silica gel, alumina, and the like, with preference given to organic acids such as acetic acid and paratoluenesulfonic acid. Examples thereof include sulfonic acids.

A solvent may not be used in the deoxidation reaction, but when a solvent is used, alcohols such as methanol, ethanol and isopropanol, acetone and methyl are used.
Ketones such as ethyl ketone, ethers such as ether, tetrahydrofuran, dioxane, aromatic hydrocarbons such as benzene, toluene, xylene, aliphatic hydrocarbons such as hexane, cyclohexane and heptane, dichloromethane, chloroform. Organic acids such as halogenated hydrocarbons, acetic acid, propionic acid, etc.
Pyridine, organic bases such as triethylamine, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide,
Examples thereof include sulfones such as sulfolane, water and the like, preferably aromatic hydrocarbons such as benzene, and organic acids such as acetic acid.

When a deoxidizing agent or deoxidizing catalyst is used, the compound (2
The ratio of 3) to the deoxidizing agent or the deoxidizing catalyst is not particularly limited, but usually 0.01 mol to 10 mol of the deoxidizing agent or the deoxidizing catalyst with respect to 1 mol of the compound (23), It is preferably 0.1 to 3 mol. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials used, the type of solvent, etc., but are usually 0 to 120 ° C., preferably 40 ° to 100 ° C., and a few minutes to a few days, preferably 10 Minutes to 1
It's 0 hours.

F-5 The F-5 step is performed in the 2H-chromenes (2
This is a step of producing chromanes (4) having an amino group by reducing the nitro group of 2) and simultaneously reducing the carbon-carbon double bond.

A catalytic reduction method is preferably used for the reduction reaction. Examples of the catalyst used for catalytic reduction include palladium-carbon, Raney-nickel, platinum oxide and the like, but palladium-carbon is preferable. The hydrogen pressure is 1 atm to 100 atm, preferably 1 atm to 6 atm. Examples of the solvent include alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, organic acids such as acetic acid, water and a mixture thereof. . The reaction temperature and reaction time will differ depending on the starting materials and solvent used, but will usually be from room temperature to 50 ° C., and from a few minutes to about 20 hours.

Thereafter, the production of α-halogenocarboxylic acid derivatives (II) (W: CH ₂ ) is achieved by the step A-4.

In addition, F-1, F-2, F-3, F-4, F-5, A-
4 and / or the final step for producing the desired thiazolidine derivative is sequentially carried out according to the desired intermediate (2
1), (22), (23), (4) and / or (I
I) (W ₁ : CH ₂ ) can be carried out without isolation.

Further, for example, the steps shown in Method F are not limited to the order shown. That is, for example, the nitro group of the compound (12) in which the 4-position of the chroman ring is a carbonyl group is first reduced, then the 4-position carbonyl group is reduced, and further dehydrated to give a 2H-chromene derivative, followed by a double bond. The reduction of the bond to obtain the amino compound (4) is the same as in the F method.

Method G Method G is similar to method F and can be used to produce a compound of formula (II) in which W is a methylene group from a compound in which the 4-position of the chroman ring is a carbonyl group. That is, it was produced by the deprotection reaction of the protecting group for the hydroxyl group at the 6-position of the chroman ring described in Method D, Method E, and Method A, and the acylation reaction of the hydroxyl group. B ₂ has the formula -S- (CH ₂ ) p
When the compound (24) or (26) showing an —S— group (wherein p represents 2,3,4) is catalytically reduced with a nickel catalyst such as Raney nickel, a compound in which the 4-position of the chroman ring is a methylene group ( 25) or (27) can be obtained respectively.

The hydrogen pressure in this reaction is 1 atm to 100 atm, preferably 1 atm to 6 atm. As the solvent, methanol,
Alcohols such as ethanol, aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, organic acids such as acetic acid, water and mixtures thereof. The reaction temperature and the reaction time will differ depending on the starting materials and solvent used, but are usually room temperature to 50.
It is several minutes to about 20 hours at 0 ° C.

Method H is a precursor of the above-mentioned compound (XV) in which W represents a carbonyl group and U represents a double bond together with a methylene group or R ¹ among the target compounds represented by the formula (I), that is, , An α-halogenocarboxylic acid derivative in which the 2-position of the chroman ring is L (L has the same meaning as described above) (XII
It can be used to manufacture I).

In the formula, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ ,
A, Ar, L, n, U and X have the same meanings as described above.

H-1 The H-1 step is equivalent to the C-2 step, and usually L is a group-
OR ³ is shown and U is a methylene group, but if necessary, L and U can form a double bond. Compound (28) has the formula O ₂ N- (Ar) -O- (CH ₂ ) _n -COX
(Wherein Ar, n and X have the same meanings as defined above), and then treated with an organic base such as sodium ethoxide or potassium t-butoxide.

H-2 The H-2 step is equivalent to the A-3 step, and the relationship between L and U is the same as described in H-1.

H-3 The H-3 step is equivalent to the A-4 step, and the relationship between L and U is the same as the description of H-1.

Raw material compound, that is, α-halogenocarboxylic acids (II)
Among these, the preferred method among the methods A to H is the A, B, C, D, E, F and H methods, and further the A, C, D, E, F and H methods. . D method, F
It is more preferable to use the method A and the method A in combination.

In the α-halogenocarboxylic acids represented by the formula (II), the carbon atom at the 2-position of the chroman ring and the α-position of the substituent A are asymmetric carbon atoms, and the isomers based on them are also included in the compound (II). To be done.

It should be noted that the α-halogenocarboxylic acid derivatives (II) thus obtained are also found to have not only a blood lipid-lowering effect but also a blood triglyceride and cholesterol-lowering effect. It is useful as a therapeutic agent for lipemia.

The α-halogenocarboxylic acid derivatives (II) having a chroman ring thus obtained are mutually converted into various hydrolysis products, transesterification products, or metals such as sodium, potassium, calcium, and aluminum as desired. It can be converted to salts, or conversely, from metal salts or from free phenols and / or free carboxylic acids to esters, amides and the like.

In particular, when the α-halogenocarboxylic acid derivative (II) is led to various desired hydrolysis products, the production of the products is accomplished as follows, for example.

The compound in which R ³ is a hydrogen atom and A is a carboxy group is a compound (II) in which R ³ is, for example, an acyl group and A is an alkoxycarbonyl group, and an alkali metal carbonate such as sodium carbonate or potassium carbonate, Hydrolysis reaction in the presence of an inorganic base such as an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or a base such as an alkali metal alcoholate such as sodium methoxide, sodium ethoxide or potassium tert-butoxide. Can be obtained by doing. Examples of the solvent include lower alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, water, and mixed solvents thereof. The ratio of the hydrolysis (II) to the inorganic base or the base is 1 to 5, preferably 2 to 3 with respect to 1 mol of the compound (II). The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials, bases, solvents and the like used, but the reaction temperature is usually -10 to 30 ° C, preferably 0 to 10 ° C, and the reaction time is several minutes to several tens hours. is there.

A compound in which R ³ is a hydrogen atom and A is an alkoxycarbonyl group is a compound (II) in which R ³ is, for example, an acyl group and A is an alkoxycarbonyl group, and sodium methoxide, sodium ethoxide, potassium tertiary butoxide It can be obtained by carrying out a solvolysis reaction in the presence of a base such as a calcalylic metal alcoholate. Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol and t-butyl alcohol, ethers such as tetrahydrofuran and dioxane, and a mixture thereof. In particular, when it is desired to retain the alkoxycarbonyl group shown in the group A of the raw material as it is, an alcoholate of an alkali metal corresponding to the alkoxy group is selected and an alcohol corresponding to the alkoxy group is used as a solvent. It is desirable to select.
Furthermore, if desired, by selecting an alcoholate of an alkali metal and an alcohol as a solvent, the alkoxycarbonyl group in the raw material can be exchanged for a desired alkoxycarbonyl group. The ratio of the starting compound (II) to the base is 1 to 3, preferably 1 to 2 with respect to 1 mol of the compound (II). Reaction temperature,
The reaction conditions such as reaction time will differ depending on the starting materials, bases, solvents, etc. used, but the reaction temperature is usually -10 to 30.
C., preferably 0 to 10.degree. C., and the reaction time is a few minutes to a few tens hours.

A compound in which R ³ is an acyl group and A is a carboxy group is a compound (II) in which R ³ is, for example, an acyl group and A is an alkoxycarbonyl group, and an alkali metal carbonate such as sodium carbonate or potassium carbonate, Hydrolysis reaction in the presence of an inorganic base such as an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or a base such as an alkali metal alcoholate such as sodium methoxide, sodium ethoxide or potassium tert-butoxide. Can be obtained by doing. Examples of the solvent include lower alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, water, and mixed solvents thereof. The ratio of the compound (II) to the inorganic base or the base is 1 to 5, preferably 1 to 2 with respect to 1 mol of the compound (II). The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials, base, solvent and the like used, but the reaction temperature is usually -10 to 30 ° C. The reaction time is preferably 0 to 10 ° C. and the reaction time is several minutes to about 10 hours.

Suitable compounds represented by the formula (II) having the above-mentioned pharmacological activity include the compounds having the following structural formulas as shown in Table 13.

In addition, there are compounds shown in Table 14 having the structural formulas shown below.

EFFECTS OF THE INVENTION The object compound of the present invention represented by the general formula (I) is
It has a high antioxidant effect on unsaturated fatty acids and their esters such as linoleic acid and ethyl linoleate, so it is expected that phospholipids, which have a high percentage of unsaturated fatty acids, can be prevented in vivo. Done: Biochem.
Biophys.Res.Commun, 95 , 734-737 (198)
In the rat liver microsomal lipid peroxidation inhibition test shown in 0), blood lipid peroxidase was not only shown to have a synergistic lipid peroxidation-lowering effect, but also in a test of experimental hyperlipidemic mice induced by alloxan. , Lowers triglyceride and cholesterol, and further has a blood glucose lowering effect in the test of genetically hyperglycemic KK mice, and exhibits an enzyme inhibitory effect in the test of measuring aldose reductase activity using bovine lens. It is a compound that exhibits extremely excellent pharmacological effects such as, and has extremely low toxicity on experimental animals such as rats, an effect of suppressing appetite, an effect of suppressing weight gain, and particularly an effect of hepatomegaly.

From the results of the above-mentioned tests, the thiazolidine derivative (I) of the present invention shows that human hyperlipidemia, diabetes and their complications,
For example, it is expected to be useful for the treatment of diabetic cataract, diabetic neuropathy and the like. As an administration method, for example, it can be orally used as tablets, capsules, powders, granules, etc., and can be parenterally administered as injections (intravenous, subcutaneous, intramuscular), suppositories, etc. For mucosal administration, eye drops and eye ointments are preferred. The dose varies depending on symptoms, age, etc., but when used as a therapeutic agent for hyperlipidemia and / or diabetes and their complications, for example, 50 mg to 5 g per day is usually orally or parenterally for adults. , Can be administered.

The following Examples and Application Regulations (R ⁹ is a compound other than hydrogen atom)
The present invention will be described more specifically with reference to reference examples.

Example 1 5- [4- (6-acetoxy-5,7,8-trimethyl-2-octylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione ethyl 3- [4- (6-acetoxy- 5,7,8-Trimethyl-2-octylchroman-2-ylmethoxy)
A mixture of 2.1 g of phenyl] -2-chloropropionate, 0.35 g of thiourea and 2.5 ml of sulfolane is heated at 120-130 ° C. for 7 hours under a nitrogen atmosphere. Benzene is added to the reaction mixture to dissolve it, and the benzene solution is washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 10: 1) to obtain the target compound (pale yellow foamy solid).

Rf value of silica gel thin layer chromatography = 0.55
(Developing solvent; benzene: ethyl acetate = 4: 1).

NMR spectrum (δppm, CDCl ₃ ): 0.7-1.0 (3H,
m), 1.1-2.0 (16H, m), 1.97 (3H, s), 2.03 (3H, s), 2.08 (3H,
s), 2,31 (3H, s), 2.60 (2H, br, t, J = 6Hz), 3.03 (1H, dd, J = 1
0 and 15Hz), 3.44 (1H, dd, J = 3 and 15Hz), 3.92 (2H,
s), 4.45 (1H, dd, J = 3 and 10Hz), 6.85 (2H, d, J = 9Hz),
7.13 (2H, d, J = 9Hz), 8.0-8.9 (1H, br., Disappeared by adding heavy water).

Example 2 5- [4- (6-acetoxy-5,7,8-trimethyl-2-octylchroman-2-ylmethoxy) benzyl] -2-iminothiazolidin-4-one In silica gel chromatography in Example 1, The portion that elutes next to the thiazolidine-2,4-dione (eluent; benzene: tetrahydrofuran = 4: 1)
From, the target compound (white powder) was obtained.

Softening point: 85-90 ° C NMR spectrum (δppm, CDCl ₃ ): 0.87 (3H, br,
t, J = 4.5Hz), 1.0-2.0 (16H, m), 1.97 (3H, s), 2.02 (3H, s),
2.08 (3H, s) 2.30 (3H, s), 2.4-2.7 (2H, m), 2.88 (1H, dd, J = 1
0 and 15Hz), 3.50 (1H, dd, J = 3 and 15Hz), 3.9 (2H, b
rs), 4.41 (1H, dd, J = 3 and 10Hz), 6.0-7.8 (2H, br., disappeared by adding heavy water), 6.83 (2H, d, J = 9Hz), 7.10 (2H, d, J = 9H
z).

Example 3 5- [4- (6-Hydroxy-5,7,8-trimethyl-2-octylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione ethyl 3- [4- (6-acetoxy- 5,7,8-Trimethyl-2-octylchroman-2-ylmethoxy)
A mixture of 2.1 g of phenyl] -2-chloropropionate, 0.35 g of thiourea and 2.5 ml of sulfolane is heated at 120-130 ° C. for 7 hours under a nitrogen atmosphere. afterwards,
A mixture of 3.6 ml of 2N hydrochloric acid and 5 ml of ethylene glycol monomethyl ether was added to the reaction mixture, and the mixture was further heated at 85-90 ° C for 5 hours. The reaction mixture is poured into water, extracted with benzene, the extract is washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 10: 1) to give the desired compound (pale yellow foamy solid).
Got

Rf value of silica gel thin layer chromatography = 0.43
(Tailing) (developing solvent; benzene: ethyl acetate =
4: 1) NMR spectrum (δppm, CDCl ₃ ): 0.7-1.0 (3H,
m), 1.1-2.1 (16H, m), 2.10 (6H, s), 2.15 (3H, s), 2.61 (2H, b
rt, J = 6Hz), 3.05 (1H, dd, J = 10 and 15Hz), 3.42 (1H, d
d, J = 3 and 15Hz), 3.92 (2H, s), 4.22 (1H, s, disappeared by adding heavy water), 4.47 (1H, dd, J = 3 and 10Hz), 6.85 (2H, d, J = 9
Hz), 7.13 (2H, d, J = 9Hz), 8.33 (1H, br.s, disappeared by addition of heavy water).

Example 4 5- [4- (6-acetoxy-2-methyl-7- (1,
1,3,3-Tetramethylbutyl) chroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione In accordance with Example 1, ethyl 3- [4- [6-acetoxy-2-methyl-7- (1 , 1,3,3-Tetramethylbutyl) chroman-2-ylmethoxy) phenyl] -2-
The target product produced from 7.0 g of chloropropionate, 1.2 g of thiourea and 9 ml of sulfolane has the following physical properties.

Softening point: 75-80 ° C (pale yellow glassy solid) NMR spectrum (δppm, CDCl ₃ ): 0.79 (9H, s),
1.36 (6H, s), 1.45 (3H, s), 1.66-2.88 (2H, nd), 1.80 (2H, n
d), 2.29 (3H, s), 2.73 (2H, br.t, J = 6Hz), 3.28 (1H, dd, J =
9 and 14Hz), 3.45 (1H, dd, J = 4 and 14Hz), 3.93 (2H,
AB type, J = 9Hz), 4.49 (1H, dd, J = 4 and 9Hz), 6.75 (1H,
s), 6.86 (1H, s), 6.90 (2H, d, J = 9Hz), 7.13 (2H, d, J = 9Hz),
8.1-8.7 (1H, br., Disappeared by adding heavy water).

Example 5 5- [4- [6-acetoxy-2-methyl-7- (1,
1,3,3-Tetramethylbutyl) chroman-2-ylmethoxy) benzyl] -2-iminothiazolidine-4-
ON According to Example 2, ethyl 3- [4-[-6-acetoxy-2-methyl-7- (1,1,3,3-tetramethylbutyl) chroman-2-ylmethoxy) phenyl] -2
-Chloropropionate 7.0 g, thiourea 1.2 g,
The target product produced from 9 ml of sulfolane has the following physical properties.

Melting point: 120-128 ° C NMR spectrum (δppm, heavy acetone): 0.78 (9H, s),
1.35 (6H, s), 1.41 (3H, s), 1.82 (2H, s), 1.90-2.17 (2H, nd),
2,26 (3H, s), 2.77 (2H, br.t, J = 6.5Hz), 2.73-3.10 (1H, n
d), 3.41 (1H, dd, J = 4 and 14Hz), 4.00 (2H, s), 4.49 (1H,
dd, J = 4 and 10Hz), 6.75 (1H, s), 6.78 (1H, s), 6.92 (2H,
d, J = 9Hz), 7.22 (2H, d, J = 9Hz), 7.4-8.6 (2H, br., disappeared by adding heavy water).

Example 6 5- [4- [6-hydroxy-2-methyl-7- (1,
1,3,3-Tetramethylbutyl) chroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione In accordance with Example 3, ethyl 3- [4- [6-acetoxy-2-methyl-7- (1 , 1,3,3-Tetramethylbutyl) chroman-2-ylmethoxy) phenyl] -2-
The target product prepared from 7 g of chloropropionate, 1.2 g of thiourea, 9 ml of sulfolane, 13 ml of 2N hydrochloric acid, and 20 ml of ethylene glycol monomethyl ether has the following physical properties.

Softening point: 80-85 ° C (pale yellow glassy) NMR spectrum (δppm, CDCl ₃ ): 0.78 (9H, s),
1.41 (9H, s), 1.60-2.30 (2H, nd), 1.91 (2H, s), 2.67 (2H, br.
t, J = 6.5Hz), 3.07 (1H, dd, J = 10 and 14Hz), 3.45 (1H, d
d, J = 4 and 14Hz), 3.93 (2H, AB type, J = 9Hz), 4.45 (1H,
s, disappeared by addition of heavy water), 4.49 (1H, dd, J = 4 and 10Hz), 6.
34 (1H, s), 6.77 (1H, s), 6.88 (2H, d, J = 9Hz), 7.17 (2H, d, J
= 9Hz), 8.4 (1H, br.s, disappeared by adding heavy water).

Example 7 5- [4- [6-acetoxy-2-methyl-4-oxo-7- (1,1,3,3-tetramethylbutyl) chroman-2-ylmethoxy) benzyl] thiazolidine-2,
4-Dione According to Example 1, ethyl 3- [4- [6-acetoxy-2-methyl-4-oxo-7- (1,1,3,3-
The target compound produced from 7.3 g of tetramethylbutyl) chroman-2-ylmethoxy) phenyl] -2-chloropropionate, 1.3 g of thiourea and 8 ml of sulfolane is
It has the following physical properties.

Softening point: 80-88 ° C (pale yellow powder) NMR spectrum (δppm, CDCl ₃ ): 0.78 (9H, s),
1.37 (6H, s), 1.53 (3H, s), 1.83 (2H, s), 2.30 (3H, s), 2.70 (1
H, d, J = 17Hz), 2.8-3.2 (1H, nd), 3.10 (1H, d, J = 17Hz), 3.4
5 (1H, dd, J = 4 and 15Hz), 4.00 and 4.12 (2H, AB type,
J = 9Hz), 4.48 (1H, dd, J = 4 and 9Hz), 6.85 (2H, d, J = 9
Hz), 7.02 (1H, s), 7.17 (2H, d, J = 9Hz), 7.51 (1H, s), 8.3-9.
0 (1H, br., Disappeared by adding heavy water).

Example 8 5- [4- [6-acetoxy-2-methyl-4-oxo-7- (1,1,3,3-tetramethylbutyl) chroman-2-ylmethoxy) benzyl] -2-iminothiazolidine- 4-one Following the procedure of Example 2, ethyl 3- [4- [6-acetoxy-2-methyl-4-oxo-7- (1,1,3,3-
The target compound produced from 7.3 g of tetramethylbutyl) chroman-2-ylmethoxy) phenyl] -2-chloropropionate, 1.3 g of thiourea and 8 ml of sulfolane is
It has the following physical properties.

Melting point 125-130 ° C NMR spectrum (δppm, heavy acetone): 0.77 (9H, s),
1.39 (6H, s), 1.53 (3H, s), 1.89 (2H, s), 2.34 (3H, s), 2.6-3.
0 (1H, nd), 2.75 (1H, d, J = 16Hz), 3.13 (1H, d, J = 16Hz), 3.4
0 (1H, dd, J = 4 and 14Hz), 4.17 (2H, s), 4.48 (1H, dd, J =
4 and 10Hz), 6.87 (2H, d, J = 9Hz), 7.01 (1H, s), 7.20 (2
H, d, J = 9Hz), 7.46 (1H, s), 7.8-8.7 (2H, br., Disappeared by adding heavy water).

Example 9 5- [4- [6-Hydroxy-2-methyl-4-oxo-7- (1,1,3,3-tetramethylbutyl) chroman-2-ylmethoxy] benzyl] thiazolidine-2,
4-dione 5- [4- [6-acetoxy-2-methyl-4-oxo-7- (1,1,3,3-tetramethylbutyl) chroman-2-ylmethoxy] benzyl] -2-iminothiazolidine- A mixture of 5.2 g of 4-one, 16 ml of 2N hydrochloric acid and 25 ml of ethyl glycol monomethyl ether is heated at 85-90 ° C for 6 hours under a nitrogen atmosphere. The reaction mixture is poured into water, extracted with benzene, the extract is washed with water,
Dry over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: benzene: ethyl acetate = 4: 1) to obtain the target compound (pale yellow foamy solid).

Softening point: 100-105 ° C NMR spectrum (δppm, CDCl ₃ ): 0.77 (9H, s),
1.43 (6H, s), 1.52 (3H, s), 2.00 (2H, s), 2.70 (1H, d, J = 17H
z), 2.8-3.2 (1H, nd), 3.12 (1H, d, J = 17Hz), 3.43 (1H, dd, J
= 4 and 15Hz), 4.00 and 4.10 (2H, AB type, J = 9Hz),
4.49 (1H, dd, J = 4 and 9Hz), 6.1 (1H, br, s, lost by addition of heavy water), 6.85 (2H, d, J = 9Hz), 6.93 (1H, s), 7.15 (2H, d , J ＝
9Hz), 7.30 (1H, s), 8.2-9.3 (1H, br., Disappeared by adding heavy water).

Example 10 5- [4- [2- (3,7-dimethyloctyl) -6-
Hydroxy-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy] benzyl] thiazolidine-
2,4-dione In accordance with Example 3, ethyl 3- [4- [6-acetoxy-2- (3,7-dimethyloctyl) -5,7,8-
Trimethyl-4-oxochroman-2-ylmethoxy]
The target compound was obtained from 1.1 g of phenyl] -2-chloropropionate, 0.2 g of thiourea, 1.5 ml of sulfolane, 5 ml of 2N hydrochloric acid, and 10 ml of ethylene glycol monomethyl ether.

Softening point: 41-45 ° C (pale yellow powder) NMR spectrum (δppm, CDCl ₃ ): 0.85 (9H, d, J
= 7Hz), 1.0-2.0 (12H, m), 2.13 (3H, s), 2.22 (3H, s), 2.55 (3
H, s), 2.65-3.2 (3H, m), 3.43 (1H, dd, J = 4 and 14Hz), 4.
05 (2H, s), 4.35-5.3 (1H, br ,, disappears by adding heavy water), 4.46 (1
H, dd, J = 4 and 10Hz), 6.83 (2H, d, J = 9Hz), 7.15 (2H, d,
J = 9Hz), 8.0-9.5 (1H, br., Disappeared by adding heavy water).

Example 11 5- [2- (6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) pyridin-5-ylmethyl] thiazolidin-2,4-dione In accordance with Example 3, ethyl 3- [2- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) pyridin-5-yl] -2-chloropionate 3.8 g, thiourea 0.77 g, sulfolane 5 0.0 m
l, ethylene glycol monomethyl ether 4.5 ml,
The desired product was obtained from 1.5 ml of concentrated hydrochloric acid and 4.5 ml of water.

Softening point: 87-94 ° C NMR spectrum (δppm, CDCl ₃ ): 1.38 (3H, s),
1.7-2.3 (2H, m), 2.06 (3H, s), 2.09 (3H, s), 2.14 (3H, s), 2.6
3 (2H, br.t, J = 6Hz), 3.10 (1H, dd, J = 15 and 7.5Hz), 3.3
3 (1H, dd, J = 15 and 4.5Hz), 4-5 (1H, br., Disappears by adding heavy water), 4.32 (3H, s), 4.47 (1H, dd, J = 7.5 and 4.5H)
z), 6.75 (1H, d, J = 9Hz), 7.46 (1H, dd, J = 9 and 3Hz), 8.
02 (1H, d, J = 3Hz).

Example 12 5- [3- (7-t-Butyl-6-hydroxy-2-methyl-4-oxochroman-2-ylmethoxy) -4-
Methylbenzyl] thiazolidine-2,4-dione According to Example 3, ethyl 3- [3- (6-acetoxy-7-t-butyl-2-methyl-4-oxochroman-2-ylmethoxy) -4-methyl. The target compound was obtained from 2.4 g of phenyl] -2-chloropropionate, 0.7 g of thiourea, 5 ml of sulfolane, 10 ml of 2N hydrochloric acid, and 15 ml of ethylene glycol monomethyl ether.

Rf value by silica gel thin layer chromatography = 0.
44 (developing solvent; benzene: ethyl acetate = 1: 1) NMR spectrum (δ ppm, CDCl ₃ ): 1.40 (9H, s),
1.57 (3H, s), 2.14 (3H, s), 2.77 (1H, d, J = 16Hz), 3.01 (1H, d
d, J = 10 and 14Hz), 3.07 (1H, d, J = 16Hz), 3.44 (1H, dd, J
= 4 and 14Hz), 3.99 and 4.13 (2H, AB type, J = 10Hz),
4.50 (1H, dd, J = 4 and 10Hz), 5.84 (1H, br, s, disappeared by adding heavy water), 6,6-6.85 (2H, nd), 6.91 (1H, s), 7.08 (1H, d , J ＝
7.5Hz), 7.31 (1H, s), 8.3-9.0 (1H, br., Disappeared by adding heavy water).

Example 13 5- [4- (6-Hydroxy-5,7,8-trimethylchromone-2-ylmethoxy) benzyl] thiazolidine-2,4-dione In accordance with Example 3, ethyl 3- [4- (6 -Acetoxy-2-hydroxy-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy) phenyl] -2-chloropropionate 2.2 g, thiourea 0.8 g, sulfolane 4.5 g, ethylene glycol monomethyl The target compound was obtained from 70 ml of ether, 8 ml of water and 4 ml of 35% hydrochloric acid.

Melting point: 249-252 ° C NMR spectrum (δppm, DMSO-d ₆ ): 2.25 (6
H, s), 2.63 (3H, s), 2.7-3.8 (2H, nd), 4.88 (1H, dd, J = 4 and 9Hz), 5.11 (2H, s), 6.28 (1H, s), 7.05 ( 2H, d, J = 9Hz),
7.24 (2H, d, J = 9Hz), 8.3-8.7 (1H, br.s, disappeared by adding heavy water).

Example 14 5- [4- [6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] 5-methylthiazolidine-2,4-dione In accordance with Example 3, ethyl 3 -[4- (6-Acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -2-chloro-2-methylpropionate 1.17 g, thiourea 0.63 g, sulfolane 3 g , Ethylene glycol monomethyl ether 10ml,
The target compound prepared from 3 ml of water and 2 ml of 35% hydrochloric acid has the following physical properties.

Softening point; 69-72 ° C NMR spectrum (δppm, CDCl ₃ ): 1.40 (3H, s),
1.72 (3H, s), 1.6-2.3 (2H, nd), 2,10 (6H, s), 2.16 (3H, s), 2.
62 (2H, br.t, J = 7Hz), 2.94 (1H, d, J = 14Hz), 3.24 (1H, d, J
= 14Hz), 3.84 and 3.97 (2H, AB type, J = 9Hz), 4.40 (1H, b
rs, disappeared by adding heavy water), 6.84 (2H, d, J = 9Hz), 7.13 (2
H, d, J = 9Hz), 8.4-8.9 (disappeared by adding 1H, br.s heavy water).

Example 15 5- [4- [6-hydroxy-4- (E) -hydroxyimino-2,5,7,8-tetramethylchroman-2-
Ilmethoxy) benzyl] thiazolidine-2,4-dione 5- [4- (6-hydroxy-2,5,7,8-tetramethyl-4) prepared by the above-mentioned Method D and then by the method similar to Example 1. -Oxochroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 5 g, hydroxylamine hydrochloride 3 g, methanol 50 g and pyridine 3
The mixture of g was stirred at room temperature for 1 week. Ethyl acetate and aqueous potassium carbonate solution were added to the reaction mixture, the organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was chromatographed on silica gel (eluent; hexane:
The target compound was obtained by subjecting to ethyl acetate = 1: 1).

Softening point: 84-100 ° C NMR spectrum (δppm, heavy acetone): 1.42 (3H,
s), 2.09 (3H, s), 2.18 (3H, s), 2.48 (3H, s), 3.03 (1H, dd, J =
9 and J = 14Hz), 3.07 (2H, s), 3.43 (1H, dd, J = 4 and J = 14Hz), 4.05 (2H, s), 4.72 (1H, dd, J = 4 and 9Hz),
6.92 (2H, d, J = 9Hz), 7.21 (2H, d, J = 9Hz), 9.7-10.5 (1H, b
rs, disappeared by adding heavy water).

Example 16 5- [4- [6-hydroxy-4- (E) -hydroxyimino-2,5,7,8-tetramethylchroman-2-
Ilmethoxy) benzyl] thiazolidine-2,4-dione 5- [4- [6-hydroxy-4- (Z) -hydroxyimino-2,5,7,8-tetramethylchroman-2-
62 mg of ilmethoxy) benzyl] thiazolidine-2,4-dione were heated in an oil bath at 140 ± 5 ° C. for 5 hours. The reaction mixture was subjected to liquid chromatography to confirm the production of the desired product (the compound of Example 15).

Example 17 5- [4- (6-Hydroxy-4- (Z) -hydroxyimino-2,5,7,8-tetramethylchroman-2-
Ilmethoxy) benzyl] thiazolidine-2,4-dione The target compound was obtained from the fraction eluted after the target compound of Example 15 in the column chromatography of Example 15.

Softening point: 100-105 ° C NMR spectrum (δppm, deuterated acetone): 1.46 (3H, s),
2.04 (3H, s), 2.18 (6H, s), 2.58 (1H, d, J = 13Hz), 2.87 (1H,
d, J = 13Hz), 3.10 (1H, dd, J = 9 and 14Hz), 3.43 (1H, dd,
J = and 14Hz), 4.01 (2H, s), 4.74 (1H, dd, J = 4 and 9H
z), 6.92 (2H, d, J = 9Hz), 7.22 (2H, d, J = 9Hz), 9.4-10.6 (1
H, br.s, disappeared by adding heavy water).

Example 18 5- [4- (6-Hydroxy-4- (Z) -hydroxyimino-2,5,7,8-tetramethylchroman-2-
Ilmethoxy) benzyl] thiazolidine-2,4-dione 5- [4- (6-hydroxy-4- (E) -hydroxyimino-2,5,7,8-tetramethylchroman-2-
27 mg of ilmethoxy) benzyl] thiazolidine-2,4-dione were heated in an oil bath at 140 ± 5 ° C. for 5 hours. The reaction mixture was subjected to liquid chromatography to confirm the production of the desired product (the compound of Example 17).

Example 19 5- [4- (6-acetoxy-4- (E) -acetoxyimino-2,5,7,8-tetramethylchroman-2-
Ilmethoxy) benzyl] thiazolidine-2,4-dione 5- [4- (6-hydroxy-4- (E) -hydroxyimino-2,5,7,8-tetramethylchroman-2-
A mixture of 1 g of ylmethoxy) benzyl] thiazolidine-2,4-dione, 1.3 g of acetic anhydride and 10 ml of pyridine was left standing at room temperature for 8 days and further heated at 60 to 80 ° C. for 8 hours. Aqueous potassium carbonate solution and ethyl acetate were added to the reaction mixture, the organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was evaporated, the residue was subjected to silica gel chromatography (eluent; hexane: ethyl acetate = 4: 1),
The target compound was obtained.

Softening point: 93-97 ° C NMR spectrum (δppm, CDCl ₃ ): 1.48 (3H, s),
2.07 (3H, s), 2.10 (3H, s), 2.22 (3H, s), 2.33 (3H, s), 2.42 (3
H, s), 3.00 (1H, d, J = 17Hz), 3.26 (1H, d, J = 17Hz), 3.0-3.3
(1H, nd), 3.41 (1H, dd, J = 4 and 14Hz), 3.91 and 4.06
(2H, AB type, J = 9Hz), 4.47 (1H, dd, J = 4 and J = 9Hz),
6.84 (2H, d, J = 9Hz), 7.14 (2H, d, J = 9Hz). Example 20 5- [4- (6-benzoyloxy-4- (E) -benzoyloxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-
2,4-dione 5- [4- (6-hydroxy-4- (E) -hydroxyimino-2,5,7,8-tetramethylchroman-2-
A mixture of 1 g of ylmethoxy) benzyl] thiazolidine-2,4-dione, 1.7 g of benzoyl bromide, 10 ml of pyridine and 5 ml of dimethylformamide was left at room temperature for 6 days and further heated at 60-80 ° C. for 8 hours. Aqueous potassium carbonate solution and ethyl acetate were added to the reaction mixture, and the organic layer was separated and dried over anhydrous sodium sulfate. Evaporate the solvent,
The residue is subjected to silica gel column chromatography (eluent;
Hexane: ethyl acetate = 4: 3) to obtain the target compound.

Softening point: 101-107 ° C NMR spectrum (δppm, CDCl ₃ ): 1.55 (3H, s),
2.14 (6H, s), 2.58 (3H, s), 2.8-3.7 (4H, nd), 3.98 and 4.1
2 (2H, AB type, J = 9Hz), 4.45 (1H, dd, J = 4 and 9Hz), 6.8
4 (2H, d, J = 9Hz), 7.14 (2H, d, J = 9Hz), 7.3-7.8 (6H, m), 7.9
-8.5 (4H, m).

Example 21 5- [4- (2,5,7,8-Tetramethyl-6-nicotinoyloxy-4- (E) -nicotinoyloxyiminochroman-2-ylmethoxy) benzyl] thiazolidine-2,4- Dione 5- [4- (6-hydroxy-4- (E) -hydroxyimino-2,5,7,8-tetramethylchroman-2-
Ilmethoxy) benzyl] thiazolidine-2,4-dione 1 g, nicotinoyl chloride hydrochloride 1.1 g, pyridine 1
A mixture of 2 ml and 12 ml of dimethylformamide was left at room temperature for 6 days and further heated at 60-80 ° C for 8 hours.
Aqueous potassium carbonate solution and ethyl acetate were added to the reaction mixture, and the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel chromatography (eluent; hexane: ethyl acetate = 2: 3), and then subjected to preparative thin layer silica gel chromatography (developing solvent; hexane: ethyl acetate = 1: 10). Then, the target compound was obtained.

Softening point; 123-130 ° C NMR spectrum (δppm, CDCl ₃ ): 1.56 (3H, s),
2.13 (3H, s), 2.17 (3H, s), 2.57 (3H, s), 2.8-3.7 (4H, nd), 3.
99 and 4.16 (2H, AB type, J = 9Hz), 4.45 (1H, dd, J = 4 and 9Hz), 6.84 (2H, d, J = 9Hz), 7.15 (1H, d, J = 9Hz), 7.4 -
7.7 (2H, m), 8.3-8.7 (2H, m), 8.7-9.0 (2H, m), 9.2-9.6 (2H,
m), 10-11 (1H, br., disappeared by addition of heavy water).

Example 22 5- [4- (7-t-butyl-6-hydroxy-4-
(E) -Hydroxyimino-2-methylchroman-2-
Ilmethoxy) benzyl] thiazolidine-2,4-dione According to Example 15, 5- [4- (7-t-butyl-6)
-Hydroxy-2-methyl-4-oxochroman-2-
The target compound (colorless crystals) prepared from 1.32 g of ylmethoxy) benzyl] thiazolidine-2,4-dione, 2.0 g of hydroxylamine hydrochloride, 0.5 ml of pyridine and 20 ml of methanol has the following physical properties.

Melting point 235-237 ° C Decomposition NMR spectrum (δppm, heavy acetone): 1.40 (12H,
s), 2.6-4.0 (1H, br., disappeared by adding heavy water), 2.98 (2H, s), 3.10
(1H, dd, J = 9 and 14Hz), 3.43 (1H, dd, J = 4 and 14H
z), 4.05 (2H, s), 4.74 (1H, dd, J = 9Hz), 6.73 (1H, s), 6.95 (2
H, d, J = 9Hz), 7.2-8.5 (1H, br., Disappears by adding heavy water), 7.25 (2
H, d, J = 9Hz), 7.30 (1H, s), 9.7-10.6 (1H, br., Disappeared by adding heavy water).

Example 23 5- [4- [6-hydroxy-4- (E) -hydroxyimino-2-methyl-7- (1,1,3,3-tetramethylbutyl) chroman-2-ylmethoxy] benzyl]
Thiazolidine-2,4-dione According to Example 15, 5- [4- [6-hydroxy-2
-Methyl-4-oxo-7- (1,1,3,3-tetramethylbutyl) chroman-2-ylmethoxy] benzyl] thiazolidine-2,4-dione 1.0 g, hydroxylamine hydrochloride 0.26 g, pyridine 0 The target compound prepared from 0.3 g of methanol and 10 ml of methanol has the following physical properties.

Softening point: 115-120 ° C (white powder) NMR spectrum (δppm, heavy acetone): 0.76 (9H, s),
1.40 (9H, s), 2.00 (2H, s), 2.5-3.6 (1H, br., Disappeared by adding heavy water), 2.98 (2H, s), 3.09 (1H, dd, J = 9 and 15Hz), 3.44 (1
H, dd, J = 4 and 15Hz), 4.03 (2H, s), 4.76 (1H, dd, J = 9H
z), 6.75 (1H, s), 6.93 (2H, d, J = 9Hz), 7.22 (2H, d, J = 9Hz),
7.25 (1H, s), 7.5-8.4 (1H, br., Disappeared by adding heavy water).

Example 24 5- [4- (6-Hydroxy-4- (E) -hydroxyimino-2-isobutyl-5,7,8-trimethylchroman-2-ylmethoxy) benzyl] thiazolidine-
2,4-dione According to Example 15, 5- [4- (6-hydroxy-2
-Isobutyl-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy) benzyl] thiazolidine-
2,4-dione 155 mg, hydroxylamine hydrochloride 60
The target product produced from 0 mg, 4 ml of ethanol, and 6 ml of pyridine has the following physical properties.

Softening point: 77-80 ° C NMR spectrum (δppm, heavy acetone): 0.97 (6H, d, J
= 6Hz), 1.6-2.3 (1H, nd), 1.78 (2H, d, J = 6Hz), 2.11 (3H,
s), 2.18 (3H, s), 2.46 (3H, s), 2.7-3.7 (1H, br., disappeared by adding heavy water), 2.8-3.2 (1H, nd), 3.09 (2H, s), 3.43 (1H, dd, J
= 4 and 14Hz), 4.05 (2H, AB type, J = 10Hz), 4.72 (1H, d
d, J = 4 and 9Hz), 6.91 (2H, d, J = 9Hz), 7.22 (2H, d, J = 9
Hz), 9.8-10.5 (1H, br.s, disappeared by adding heavy water).

Example 25 5- [4- [2- (3,7-dimethyloctyl) -6-
Hydroxy-4- (E) -hydroxyimino-5,7,
8-Trimethylchroman-2-ylmethoxy] benzyl] thiazolidine-2,4-dione In accordance with Example 15, 5- [4- [2- (3,7-dimethyloctyl) -6-hydroxy-5,7, 8-Trimethyl-4-oxochroman-2-ylmethoxy] benzyl] thiazolidine-2,4-dione 150 mg, hydroxylamine hydrochloride 36 mg, pyridine 41 mg, methanol 2
The target compound produced from ml has the following physical properties.

Softening point: 55-60 ° C. (pale yellow powder) NMR spectra _{(δppm, CDCl 3): 0.83} (9H, d, J
= 7Hz), 1.0-2.0 (12H, m), 2.10 (3H, s), 2.18 (3H, s), 2.41 (3
H, s), 2.9-3.2 (1H, nd), 2.92 (1H, d, J = 17Hz), 3.2-3.55 (1
H, nd), 3.23 (1H, d, J = 17Hz), 3.94 (2H, s), 4.3-4.8 (1H, n
d), 4.46 (1H, dd, J = 4 and 10Hz), 6.83 (2H, d, J = 9Hz),
7.15 (2H, d, J = 9Hz), 7.8-8.9 (2H, br., Disappeared by adding heavy water).

Example 26 5- [4- (6-Hydroxy-2,5,7,8-tetramethyl-4- (E) -methoxyiminochroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 5- [ 4- (6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (1 g), a mixture of 0.6 g of methoxyamine hydrochloride and 5 g of methanol was added. It was left at room temperature for 10 days. Ethyl acetate and aqueous potassium carbonate solution were added to the reaction mixture, the organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate =).
3: 1) to obtain the target compound.

Softening point: 72-76 ° C NMR spectrum (δppm, CDCl ₃ ): 1.41 (3H, s),
2.08 (3H, s), 2.17 (3H, s), 2.50 (3H, s), 2.88 and 3.08 (2
H, AB type, J = 17Hz), 3.00 (1H, dd, J = 9 and 14Hz), 3.42
(1H, dd, J = 4 and 14Hz), 3.92 (2H, s), 3.96 (3H, s), 4.2-
4.9 (1H, br), 4.45 (1H, dd, J = 4 and 9Hz), 6.83 (2H, d, J
= 9Hz), 7.12 (2H, d, J = 9Hz).

Example 27 5- [4- (4- (E) -benzyloxyimino-6-
Hydroxy-2,5,7,8-tetramethylchroman-
2-ylmethoxy) benzyl] thiazolidine-2,4-
Dione 5- [4- (6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 1 g, benzyloxyamine hydrochloride 1.2 g and A mixture of 10 g of methanol was left at room temperature for 7 days. Ethyl acetate and aqueous potassium carbonate solution were added to the reaction mixture, the organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 3: 1) to obtain the target compound.

Softening point: 64-69 ° C NMR spectrum (δppm, CDCl ₃ ): 1.40 (3H, s),
2.06 (3H, s), 2.16 (3H, s), 2.41 (3H, s), 2.92 and 3.18 (2
H, AB type, J = 17Hz), 3.02 (1H, dd, J = 9 and 14Hz), 3.42
(1H, dd, J = 4 and 14Hz), 3.90 (2H, s), 4.43 (1H, dd, J =
4 and 9Hz), 5.19 (2H, s), 6.82 (2H, d, J = 9Hz), 7.11 (2H,
d, J = 9Hz), 7.2-7.5 (5H, m).

Example 28 5- [4- (4- (E) -t-Butoxycarbonylmethoxyimino-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4- Dione 5- [4- (6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 1 g, t-butoxycarbonylmethoxyamine.p- A mixture of 2.1 g of toluene sulfonate, 5 g of methanol and 0.6 g of pyridine was allowed to stand at room temperature for 7 days. Ethyl acetate and aqueous potassium carbonate solution were added to the reaction mixture, the organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 3: 1) to obtain the target compound.

Softening point: 76-80 ° C NMR spectrum (δppm, CDCl ₃ ): 1.44 (3H, s),
1.49 (9H, s), 2.07 (3H, s), 2.17 (3H, s), 2.43 (3H, s), 3.02 (1
H, dd, J = 9 and 14Hz), 3.08 (2H, AB type, J = 17Hz), 3.42
(1H, dd, J = 4 and 14Hz), 3.96 (2H, s), 4.43 (1H, dd, J =
4 and 9 Hz), 4.57 (2H, s), 4.9-6.1 (2H, br., Disappeared by addition of heavy water), 6.84 (2H, d, J = 9Hz), 7.10 (2H, d, J = 9Hz).

Example 29 5- [4- (6-hydroxy-2,5,7,8-tetramethyl-2H-chromen-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 5- [4- (4,6 -Dihydroxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) benzyl]
A mixture of thiazolidine-2,4-dione 140 mg, p-toluenesulfonic acid 10 mg, benzene 10 ml and dimethylformamide 0.5 ml is heated under reflux for 1 hour. After cooling, the reaction solution is washed with a saturated aqueous solution of sodium hydrogen carbonate and then with water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 4: 1) to obtain the target compound.

Softening point: 163-176 ° C NMR spectrum (δppm, heavy acetone): 1.50 (3H, s),
2.02 (3H, s), 2.12 (3H, s), 2.18 (3H, s), 3.06 (1H, dd, J = 9
And 14Hz), 3.40 (1H, dd, J = 4 and 14Hz), 3.94 (1H, d,
J = 10Hz), 4.05 (1H, d, J = 10Hz), 4.70 (1H, dd, J = 4 and
9Hz), 5.75 (1H, d, J = 10Hz), 6.72 (1H, d, J = 10Hz), 6.85 (2
H, d, J = 9Hz), 7.19 (2H, d, J = 9Hz).

Example 30 2- [4- (2,4-Dioxothiazolidin-5-ylmethyl) phenoxymethyl] -2,5,7,8-tetramethylchroman-6-ylhydrogen succinate The above Method A followed by 1.0 g of 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione prepared in the same manner as in Example 1, Succinic anhydride 0.3
A mixture of 1 g and 1 ml pyridine was left overnight at room temperature. The reaction mixture was washed 3 times with 10 ml of cyclohexane,
The obtained insoluble matter was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 5: 1 to 1: 1).
And the target compound was obtained.

Melting point: 197-202 ° C NMR spectrum (δppm, heavy pyridine): 1.36 (3H, s),
1.5-2.3 (2H, m), 2.10 (6H, s), 2.14 (3H, s), 2.5 (2H, br.t, J
= 6Hz), 2.7-3.35 (5H, m), 3.60 (1H, dd, J = 4 and 15Hz),
3.95 and 4.05 (2H, AB type, J = 9Hz), 4.90 (1H, dd, J = 4)
And 9 Hz), 6.98 (2H, d, J = 9Hz), 7.30 (2H, d, J = 9Hz).

Sodium salt 246 mg of this succinate is suspended in 100 ml of methanol and 1 ml of 2.5% sodium methoxide methanol solution is added at room temperature. After removing a small amount of insoluble matter by filtration, methanol is distilled off under reduced pressure. The obtained residue was washed with ether to obtain a sodium salt.

Melting point: 178-180 ° C Example 31 5- [4- (4-Carboxymethoxyimino-6-hydroxy-2,5,7,8-tetramethylchroman-2-
Ilmethoxy) benzyl] thiazolidine-2,4-dione 5- [4- (4-t-butoxycarbonylmethoxyimino-6-hydroxy-2,5, obtained in Example 28.
7,8-Tetramethicchromen-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 0.7 g and 4N
A mixture of 7 ml of hydrogen chloride dioxane solution is left at room temperature for 15 hours. After completion of the reaction, the solvent was distilled off and the obtained residue was washed with warm water to obtain the desired product.

Softening point: 75-85 ° C NMR spectrum (δppm, DMSO-d ₆ ): 1.33 (3
H, s), 1.98 (3H, s), 2.09 (3H, s), 2.34 (3H, s), 2.9-3.5 (2H,
m), 3.0 (2H, s), 4.02 (2H, s), 4.65 (2H, s), 4.84 (H, dd, J = 4
And 9Hz), 6.90 (2H, d, J = 9Hz), 7.17 (2H, d, J = 9Hz), 7.5
-7.95 (1H, br, disappeared by adding heavy water).

Example 32 2- [4- (2,4-Dioxothiazolidin-5-ylmethyl) phenoxymethyl] -2,5,7,8-tetramethyl-4-oxochroman-6-yloxyacetic acid 2-
Methoxyethyl 3- [4- (6-t-butoxycarbonylmethoxy-
2,5,7,8-tetramethyl-4-oxochroman-
A mixture of 13 g of ethyl 2-ylmethoxy) phenyl] -2-chloropropionate, 2.6 g of thiourea and 15 ml of sulfolane was heated at 120 to 130 ° C. for 5 hours in a nitrogen stream. Then, 30 ml of 2N hydrochloric acid and 60 ml of 2-methoxyethanol were added, and the mixture was heated at 110 ° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 4: 1) to obtain the title transesterified thiazolidine derivative.

Rf value (hereinafter, shown by silica gel thin layer chromatography): 0.14 (developing solvent; benzene: ethyl acetate = 4: 1) NMR spectrum (δ ppm, CDCl ₃ ): 1.50 (3H, s),
2.10 (3H, s), 2.26 (3H, s), 2.45-2.8 (1H, nd), 2.56 (3H, s),
2.9-3.25 (1H, nd), 3.07 (1H, d, J = 16Hz), 3.40 (3H, s), 3,4-
3.6 (1H, nd), 3.6-3.75 (2H, m), 3.98 and 4.11 (2H, AB type,
J = 10Hz), 4.3-4.45 (2H, m), 4.34 (2H, s), 4.45-4.6 (1H, n
d), 6.85 (2H, d, J = 9Hz), 7.16 (2H, d, J = 9Hz), 8.7-9.3 (1H,
br.).

Example 33 5- [4- (6-Ethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy] benzyl] thiazolidine-2,4-dione According to Example 32, 2-chloro- 3- [4- (6-ethoxy-2,5,7,8-tetramethylchroman-2-
Ilemethoxy] phenyl] ethyl propionate 5.1
g, thiourea 1 g, sulfolane 6 ml, 2N hydrochloric acid 16 ml,
The target compound was obtained from 5 ml of 2-methoxyethanol.

Melting point: 56-60 ° C. Mass spectrum (m / e): 469 (M ⁺ ) NMR spectrum (δppm, CDCl ₃ ): 1.39 (3H, t, J
= 7Hz), 1.41 (3H, s), 1.7-2.1 (2H, nd), 2.07 (3H, s), 2.14 (3
H, s), 2.17 (3H, s), 2.61 (2H, br, t, J = 7Hz), 3.05 (1H, dd, J
= 10 and 14Hz), 3.45 (1H, dd, J = 4 and 14Hz), 3.72 (2
H, q, J = 7Hz), 3.87 and 3.97 (2H, AB type, J = 9Hz), 4.47
(1H, dd, J = 4 and 10Hz), 6.87 (2H, d, J = 9Hz), 7.14 (2H,
d, J = 9Hz), 8.6-8.8 (1H, br., disappeared by adding heavy water).

Example 34 2- [4- (2,4-Dioxothiazolidin-5-ylmethyl) phenoxymethyl] -4-hydroxy-2,
5,7,8-Tetramethylchroman-6-yloxyacetic acid 2-methoxyethyl 2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -2,5,7,8-tetramethyl -4-oxochroman-6-yloxyacetic acid 2-
A mixture of 1.2 g of methoxyethyl and 20 ml of methyl alcohol was ice-cooled, 1.5 g of sodium borohydride was added, and the mixture was stirred with ice-cooling for 1 hour. The reaction mixture was poured into ice water, neutralized with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a pale yellow powdery target compound.

Rf value: 0.20 (developing solvent; benzene: ethyl acetate =
1: 1) Mass spectrum (m / e): 573 (M ⁺ ) Example 35 2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -2,5,7,8- Methyl tetramethyl-2H-chromen-6-yloxyacetate 2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -4-hydroxy-2,
A mixture of 970 mg of 2-methoxyethyl 5,7,8-tetramethylchroman-6-yloxyacetate, 50 mg of p-toluenesulfonic acid, 10 ml of benzene and 1 ml of dioxane was heated under reflux for 1 hour in a nitrogen stream. Reaction mixture 5
% Aqueous sodium bicarbonate solution, then washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 7: 3) to give the title methyl ester.

Rf value: 0.74 (developing solvent; benzene: ethyl acetate =
1: 1) NMR spectrum (δppm, deuterated acetone): 1.51 (3H, s),
2.01 (3H, s), 2.14 (3H, s), 2.22 (3H, s), 3.07 (1H, dd, J = 9
And 14Hz), 3.42 (1H, dd, J = and 14Hz), 3.74 (3H, s),
4.03 (2H, s), 4.32 (2H, s), 4.73 (1H, dd, J = 4 and 9Hz),
5.80 (1H, d, J = 10Hz), 6.70 (1H, d, J = 10Hz), 6.86 (2H, d, J
= 9Hz), 7.20 (2H, d, J = 9Hz).

Example 36 2- [4- (2,4-Dioxothiazolidin-5-ylmethyl) phenoxymethyl] -2,5,7,8-tetramethyl-2H-chromen-6-yloxyacetic acid 2-methoxyethyl Example In column chromatography at 35, the target compound was obtained from the fraction eluted after the methyl ester in the same example.

Rf value: 0.59 ((developing solvent; benzene: ethyl acetate = 1: 1) NMR spectrum (δ ppm, heavy acetone): 1.52 (3H, s),
2.02 (3H, s), 2.16 (3H, s), 2.23 (3H, s), 3.09 (1H, dd, J = 9
And 15Hz), 3.30-3.60 (1H, nd), 3.32 (3H, s), 3.5-3.7 (2
H, m), 4.04 (2H, s), 4.25-4.45 (2H, m), 4.35 (2H, s), 4.75 (1
H, dd, J = 4 and 9Hz), 5.82 (1H, d, J = 10Hz), 6.72 (1H, d,
J = 10Hz), 6.88 (2H, d, J = 9Hz), 7.21 (2H, d, J = 9Hz).

Example 37 5- [4- [6- (2-hydroxyethoxy) -2,
5,7,8-Tetramethyl-2H-chromen-2-ylmethoxy] benzyl] thiazolidine-2,4-dione From the fraction eluted after the 2-methoxyethyl ester in silica gel column chromatography in Example 36. The title ether compound was obtained.

Rf value: 0.44 ((developing solvent; benzene: ethyl acetate = 1: 1) NMR spectrum (δ ppm, heavy acetone): 1.51 (3H, s),
2.01 (3H, s), 2.15 (3H, s), 2.21 (3H, s), 3.08 (1H, dd, J = 9
And 14Hz), 3.42 (1H, dd, J = 4 and 14Hz), 3.6-3.95 (4
H, m), 4.03 (2H, s), 4.74 (1H, dd, J = 4 and 9Hz), 5.78 (1
H, d, J = 10Hz), 6.71 (1H, d, J = 10Hz), 6.88 (2H, d, J = 9Hz),
7.21 (2H, d, J = 9Hz).

Example 38 2- [4- (2,4-Dioxothiazolidin-5-ylmethyl) phenoxymethyl] -2,5,7,8-tetramethylchroman-6-yloxyacetic acid 2-methoxyethyl 2- [4- (2,4-Dioxothiazolidin-5-ylmethyl) phenoxymethyl] -2,5,7,8-tetramethyl-2H-chromen-6-yloxyacetic acid 2-methoxyethyl 260 mg, 10% palladium carbon 300 mg,
A mixture of 50 ml of ethanol and 50 ml of ethanol was shaken for 10 hours at a hydrogen pressure of 3-5 atm using a Parr hydrogenator. After the palladium carbon was filtered off, the filtrate was concentrated under reduced pressure to obtain the target substance as a colorless oil.

Rf value: 0.34 (developing solvent; benzene: ethyl acetate =
2: 1) NMR spectrum (δppm, CDCl ₃ ): 1.40 (3H, s),
1.75-2.15 (2H, nd), 2.06 (3H, s), 2.14 (3H, s), 2.18 (3H, s),
2.61 (2H, br.t, J = 7Hz), 3.05 (1H, dd, J = 9 and 14Hz),
3.35-3.8 (3H, nd), 3.39 (3H, s), 3.86 and 3.96 (2H, AB
Type, J = 10Hz), 4.25-4.6 (3H, nd), 4.34 (2H, s), 6.87 (2H,
d, J = 9Hz), 7.15 (2H, d, J = 9Hz), 8.35-8.8 (1H, br., disappeared by adding heavy water).

Example 39 5- [4- [6- (2-hydroxyethoxy) -2,
5,7,8-Tetramethylchroman-2-ylmethoxy] benzyl] thiazolidine-2,4-dione In accordance with Example 38, 5- [4- [6- (2-hydroxyethoxy) -2,5,7 , 8-Tetramethyl-2H-
The target compound was obtained from 0.35 g of chromen-2-ylmethoxy] benzyl] thiazolidine-2,4-dione, 0.3 g of 10% palladium carbon, and 10 ml of ethyl alcohol.

Rf value: 0.45 (developing solvent; benzene: ethyl acetate =
1: 1) NMR spectrum (δppm, CDCl ₃ ): 1.41 (3H, s),
1.7-2.2 (2H, nd), 2.07 (3H, s), 2.13 (3H, s), 2.18 (3H, s), 2.
61 (2H, br.t, J = 7Hz), 3.05 (1H, dd, J = 9 and 14Hz), 3.4
4 (1H, dd, J = 4 and 14Hz), 3.7-4.1 (6H, m), 4.47 (1H, dd,
J = 4 and 9Hz), 4.85-5.2 (2H, br), 6.87 (2H, d, J = 9H
z), 7.14 (2H, d, J = 9Hz) Example 40 2- [4- (2,4-Dioxothiazolidin-5-ylmethyl) phenoxymethyl] -2,5,7,8-tetramethyl-4 -Oxochroman-6-yloxyacetate ethyl.

2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] obtained in Example 44.
A mixture of 0.5 g of -2,5,7,8-tetramethyl-4-oxochroman-6-yloxyacetic acid, 0.5 ml of 4N hydrogen chloride dioxane solution and 5 ml of ethyl alcohol was left overnight at room temperature. The reaction mixture was poured into water, neutralized with sodium bicarbonate and then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was subjected to preparative silica gel thin layer chromatography (developing solvent; benzene: ethyl acetate = 7: 3).
The target compound was obtained.

Rf value: 0.70 (developing solvent; benzene: ethyl acetate =
1: 1) NMR spectrum (δppm, CDCl ₃ ): 1.33 (3H, t, J
= 7Hz), 1.50 (3H, s), 2.10 (3H, s), 2.26 (3H, s), 2.57 (3H,
s), 2.55-2.8 (1H, nd), 3.06 (1H, d, J = 16Hz), 3.07 (1H, dd, J
= 9 and 14Hz), 3.45 (1H, dd, J = 4 and 14Hz), 4.00 and 4.11 (2H, AB type, J = 10Hz), 4.29 (2H, s), 4.31 (2H, q, J)
= 7Hz), 4.48 (1H, dd, J = 4 and 9Hz), 6.85 (2H, d, J = 9H
z), 7.16 (2H, d, J = 9Hz), 8.3-8.9 (1H, br).

Application Example 1 5- [4- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2,
4-Dioxothiazolidine-3-t-butyl acetate 5- [4- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 1 g, anhydrous Potassium carbonate 0.4
To a mixture of 3 g and 8 ml of acetone, 0.87 g of t-butyl bromoacetate was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 2 hours and left for another 2 days. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography (eluent: benzene) to obtain the target compound.

Rf value: 0.6 (developing solvent; benzene: ethyl acetate = 1
0: 1) NMR spectrum (δppm, CDCl ₃ ): 1.41 (3H, s),
1.47 (9H, s), 1.7-2.1 (2H, nd), 1.98 (3H, s), 2.02 (3H, s), 2.
07 (3H, s), 2.30 (3H, s), 2.62 (2H, br.t, J = 7Hz), 2.98 (1H, d
d, J = 10 and 14Hz), 3.55 (1H, dd, J = 4 and 14Hz), 3.8
6 and 3.97 (2H, AB type, J = 9Hz), 4.19 (2H, s), 4.45 (1H, d
d, J = 4 and 10Hz), 6.86 (2H, d, J = 9Hz), 7.15 (2H, d, J =
9Hz).

Application Example 2 5- [4- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2,
4-Dioxothiazolidine-3-methyl acetate According to Application Example 1, 5- [4- (6-acetoxy-2,
5,7,8-Tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 2.4
g, methyl bromoacetate 1.5g, potassium carbonate 1.5g
The colorless oily target product was obtained from 25 ml of acetone.

Rf value: 0.26 ((developing solvent; benzene: ethyl acetate = 20: 1) NMR spectrum (δ ppm, CDCl ₃ ): 1.42 (3H, s),
1.8-2.25 (2H, nd), 1.98 (3H, s), 2.02 (3H, s), 2.08 (3H, s),
2.30 (3H, s), 2.64 (2H, br.t, J = 7Hz), 3.01 (1H, dd, J = 10 and 14Hz), 3.54 (1H, dd, J = 4.5 and 14Hz), 3.75 (3H, s),
3.87 and 4.00 (2H, AB type, J = 9Hz), 4.31 (2H, s), 4.50 (1
H, dd, J = 4.5 and 10Hz), 6.89 (2H, d, J = 9Hz), 7.17 (2H,
d, J = 9Hz).

Application Example 3 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2,
4-Dioxothiazolidine-3-t-butyl acetate According to Application Example 1, 5- [4- (6-hydroxy-2,
5,7,8-Tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 1 g, anhydrous potassium carbonate 0.47 g, t-butyl bromoacetate 0.
The target compound produced from 93 g and 8 ml of acetone has the following physical properties.

Rf value: 0.52 ((developing solvent; benzene: ethyl acetate = 10: 1) NMR spectrum (δ ppm, CDCl ₃ ): 1.42 (3H, s),
1.48 (9H, s), 1.7-2.15 (2H, nd), 2.11 (6H, s), 2.16 (3H, s),
2.64 (2H, br.t, J = 7Hz), 2.99 (1H, dd, J = 10 and 14Hz),
3.56 (1H, dd, J = 4 and 14Hz), 3.85 and 3.98 (2H, AB
Type, J = 9Hz), 4.21 (2H, s), 4.24 (1H, s), 4,46 (1H, dd, J =
4 and 10Hz), 6.88 (2H, d, J = 9Hz), 7.15 (2H, d, J = 9H)
z).

Application Example 4 5- [4- (6-t-butoxycarbonylmethoxy-
2,5,7,8-Tetramethylchroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-
3,5-Diacetate di-t-butyl 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 1 g, anhydrous carbonic acid Potassium 0.9
To a mixture of 4 g and 10 ml of acetone, 1.9 g of t-butyl bromoacetate was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into ice water and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 20: 1) to obtain the target compound.

Rf value: 0.54 ((developing solvent; cyclohexane: ethyl acetate = 4: 1) NMR spectrum (δ ppm, CDCl ₃ ): 1.44 (9H, s),
1.48 (12H, s), 1.54 (9H, s), 1.8-2.1 (2H, nd), 2.07 (3H, s),
2.16 (3H, s), 2.20 (3H, s), 2.5-2.7 (2H, m), 2.9-3.15 (2H,
m), 3.24 (2H, s), 3.93 (2H, br.s), 4.13 (2H, s), 4.17 (2H, s),
6.85 (1H, br.d, J = 9Hz), 7.15 (1H, br.d, J = 9Hz).

Mass spectrum (m / e): 7.83 (M ⁺ ) Application Example 5 5- [4- (6-t-butoxycarbonylmethoxy)-
2,5,7,8-Tetramethylchroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3
-Acetic acid-t-butyl In the separation step by column chromatography of Application Example 4, the target compound was obtained from the portion eluted next to the t-butyl ester.

Rf value: 0.42 ((developing solvent; cyclohexane: ethyl acetate = 4: 1) NMR spectrum (δ ppm, CDCl ₃ ): 1.42 (3H, s),
1.48 (3H, s), 1.54 (9H, s), 1.7-2.1 (2H, nd), 2.06 (3H, s), 2.
15 (3H, s), 2.19 (3H, s), 2.61 (2H, br.t, J = 7Hz), 2.99 (1H, d
d, J = 10 and 14Hz), 3.56 (1H, dd, J = 4 and 14Hz), 3.8
7 and 3.96 (2H, AB type, J = 9Hz), 4,17 (2H, s), 4,20 (2H,
s), 4.46 (1H, dd, J = 4 and 10Hz), 6.87 (2H, d, J = 9Hz),
7.15 (2H, d, J = 9Hz).

Mass spectrum (m / e): 669 (M ⁺ ) Application Example 6 5- [4- [6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy) benzyl] -2, 4-dioxothiazolidine-3-acetic acid t-
Butyl According to Application Example 1, 5- [4- (6-hydroxy-2,
5,7,8-Tetramethyl-4-oxochroman-2-
Ilmethoxy) benzyl] thiazolidine-2,4-dione 1 g, anhydrous potassium carbonate 0.45 g, bromoacetic acid t-
The target compound produced from 0.9 g of butyl and 8 ml of acetone has the following physical properties.

Softening point: 170-180 ° C NMR spectrum (δppm, deuterated acetone): 1.46 (9H, s),
1.50 (3H, s), 2.10 (3H, s), 2.22 (3H, s), 2.5-2.8 (1H, nd), 2.
54 (3H, s), 3.03 (1H, dd, J = 10 and 14Hz), 3.04 (1H, d, J =
16Hz), 3.53 (1H, dd, J = 4 and 14Hz), 4.16 (2H, s), 4.22
(2H, s), 4.82 (1H, dd, J = 4 and 10Hz), 6.96 (2H, d, J = 9H
z), 7.25 (2H, d, J = 9Hz).

Application Example 7 5- [4- (6-t-butoxycarbonylmethoxy-
2,5,7,8-tetramethyl-4-oxochroman-
Ilmethoxy) benzyl] -2,4-dioxothiazolidine-3,5-di-t-butyl diacetate According to Application Example 4, 5- [4- (6-hydroxy-2,
5,7,8-Tetramethyl-4-oxochroman-2-
The target compound was obtained from 1.5 g of ylmethoxy) benzyl] -thiazolidine-2,4-dione, 1.3 g of anhydrous potassium carbonate, 5.4 g of t-butyl bromoacetate and 10 ml of acetone.

Rf value: 0.57 (developing solvent; cyclohexane: ethyl acetate = 7: 3) NMR spectrum (δppm, CDCl ₃ ): 1.42 (9H, s),
1.46 (9H, s), 1.48 (3H, s), 1.52 (9H, s), 2.10 (3H, s), 2.26 (3
H, s), 2.55-3.20 (4H, nd), 2.56 (3H, s), 3.23 (2H, s), 3.97 and 4.08 (2H, AB type, J = 10Hz), 4.12 (2H, s), 4.16 (2H, s),
6.82 (2H, d, J = 9Hz), 7.15 (2H, d, J = 9Hz).

Mass spectrum (m / e): 797 (M ⁺ ) Application Example 8 5- [4- (6-t-butoxycarbonylmethoxy-
2,5,7,8-tetramethyl-4-oxochroman-
2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3-t-butyl acetate 5- [4- (6-t-butoxycarbonylmethoxy-2,5,7,8-tetra obtained in Application Example 7] Methyl-4-oxochroman-2-ylmethoxy) benzyl] -2,4-
The target compound was obtained from the portion eluting next to dioxothiazolidine-3,5-diacetate di-t-butyl.

Rf value: 0.46 (developing solvent; cyclohexane: ethyl acetate = 7: 3) NMR spectrum (δppm, CDCl ₃ ): 1.47 (9H, s),
1.50 (3H, s), 1.53 (9H, s), 2.10 (3H, s), 2.26 (3H, s), 2.56 (3
H, s), 2.6-3.2 (3H, nd), 3.57 (1H, dd, J = 4 and 14Hz), 3.
98 and 4.11 (2H, AB type, J = 10Hz), 4.17 (2H, s), 4.20 (2
H, s), 4.47 (1H, dd, J = 4 and 10Hz), 6,86 (2H, d, J = 9H
z), 7.16 (2H, d, J = 9Hz).

Mass spectrum (m / e): 683 (M ⁺ ) Application example 9 3-Ethyl-5- [4- (6-hydroxy-2,5,5)
7,8-Tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione According to Application Example 1, 5- [4- (6-hydroxy-2,
5,7,8-Tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 0.58
g, anhydrous potassium carbonate 0.27 g, ethyl iodide 0.6
The target compound was obtained from g and 5 ml of acetone.

Rf value: 0.30 (developing solvent; benzene: ethyl acetate =
20: 1) NMR spectrum (δppm, CDCl ₃ ): 1.09 (3H, t, J
= 7Hz), 1.40 (3H, s), 1.7-2.2 (2H, nd), 2.09 (6H, s), 2.14 (3
H, s), 2.62 (2H, br, t, J = 7Hz), 3.02 (1H, dd, J = 9 and 14
Hz), 3.25-3.5 (1H, nd), 3.59 (2H, q, J = 7Hz), 3.83 and 3.
96 (2H, AB type, J = 10Hz), 4.23 (1H, s, disappears by adding heavy water), 4.
36 (1H, dd, J = 4 and 9Hz), 6.84 (2H, d, J = 9Hz), 7.11 (2
H, d, J = 9Hz).

Application Example 10 5- [4- (6-hydroxy-4-hydroxyimino-
2,5,7,8-Tetramethylchroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3
-T-butyl acetate 5- [4- (6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3-acetic acid t-
Butyl 0.5 g, hydroxylamine hydrochloride 0.25 g,
2 parts of a mixture of 0.25 g of pyridine and 5 ml of methanol
It was left for 2 days at 5 to 30 ° C. Ethyl acetate and aqueous potassium carbonate solution were added to the reaction mixture, and the organic layer was separated.
The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 9: 1) to obtain the target compound.

Rf value: 0.55 (developing solvent; benzene: ethyl acetate =
4: 1) NMR spectrum (δ ppm, deuterated acetone): 1.42 (3H, s),
1.45 (9H, s), 2.07 (3H, s), 2.17 (3H, s), 2.46 (3H, s), 3.03 (1
H, dd, J ＝ 10 and 13.5Hz), 3.07 (2H, s), 3.55 (1H, dd, J ＝
4 and 13.5Hz), 4.06 (2H, s), 4.18 (2H, s), 4.83 (1H, dd, J
= 4 and 10Hz), 6.94 (2H, d, J = 9Hz), 7.25 (2H, d, J = 9H)
z), 10.2 (1H, br, s, disappeared by adding heavy water).

Example 41 2- [4- (2,4-Dioxothiazolidin-5-ylmethyl) phenoxymethyl] -4-hydroxyimino-
2,5,7,8-Tetramethylchroman-6-yloxyacetic acid 2-methoxyethyl 2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -2,5,7,8- Tetramethyl-4-oxochroman-6-yloxyacetic acid 2-
Methoxyethyl 0.6 g, hydroxylamine hydrochloride 0.
2 g of a mixture of 3 g, pyridine 0.3 g and methanol 6 ml
It was left for 2 days at 5 to 30 ° C. Ethyl acetate and aqueous potassium carbonate solution were added to the reaction mixture, and the organic layer was separated.
The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 7: 3) to obtain the target compound.

Rf value: 0.32 (tailing) [developing solvent; benzene: ethyl acetate = 3: 2] NMR spectrum (δ ppm, deuterated acetone): 1.43 (3H, s),
2.06 (3H, s), 2.20 (3H, s), 2.46 (3H, s), 2.8-3.55 (2H, nd),
3.10 (2H, AB type, J = 13.5Hz), 3.32 (3H, s), 3.55-3.7 (2H,
m), 4.08 (2H, AB type, J = 6Hz), 4.25-4.4 (2H, m), 4.34 (2H,
s), 4.76 (1H, dd, J = 9 and 9Hz), 6.93 (2H, d, J = 9Hz), 7.
24 (2H, d, J = 9Hz), 10.0-10.6 (1H, br., Disappeared by adding heavy water).

Application Example 11 5- [4- (6-t-butoxycarbonylmethoxy-4
-Hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3-t-butylacetate 5- [4- (6-t-butoxycarbonylmethoxy) −
2,5,7,8-Tetramethyl-4-oxochroman-
2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3-t-butyl acetate (0.5 g), hydroxylamine hydrochloride (0.2 g), pyridine (0.2 g) and methanol (5 ml) were allowed to stand at 25-30 ° C for 5 days. did. Ethyl acetate and aqueous potassium carbonate solution were added to the reaction mixture,
The organic layer was separated. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 20: 1).
The target compound was obtained.

Rf value: 0.43 (developing solvent; benzene: ethyl acetate =
10: 1) NMR spectrum (δppm, CDCl ₃ ): 1.45 (3H, s),
1.47 (9H, s), 1.54 (9H, s), 2.07 (3H, s), 2.23 (3H, s), 2.47 (3
H, s), 2.85-3.15 (1H, nd), 3.08 (2H, s), 3.57 (1H, dd, J = 4
And 13.5Hz), 3.97 (2H, s), 4.20 (4H, s), 4.46 (1H, dd, J =
4 and 9Hz), 6.87 (2H, d, J = 9Hz), 7.15 (2H, d, J = 9Hz),
7.5-8.05 (1H, br.).

Application Example 12 5- [4- (6-t-butoxycarbonylmethoxy-4
-Hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3,5-diacetic acid di-t-butyl 5- [4- (6- t-butoxycarbonylmethoxy-
2,5,7,8-Tetramethyl-4-oxochroman-
A mixture of 2-ylmethoxy] benzyl] -2,4-dioxothiazolidine-3,5-di-t-butyl diacetate 350 mg, hydroxylamine hydrochloride 122 mg, pyridine 122 mg and methanol 4 ml was left at 25-30 ° C for 5 days. . Ethyl acetate and aqueous potassium carbonate solution were added to the reaction mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate =).
20: 1) to give the desired compound.

Rf value: 0.48 (developing solvent; benzene: ethyl acetate =
10: 1) NMR spectrum (δppm, CDCl ₃ ): 1.45 (21H,
s), 1.53 (9H, s), 2.08 (3H, s), 2.23 (3H, s), 2.47 (3H, s), 2.9
-3.2 (2H, nd), 3.07 (2H, br.s), 3.22 (2H, s), 3.95 (2H, br.
s), 4.11 (2H, s) 4.18 (2H, s), 6.83 (2H, d, J = 9Hz), 7.13 (2H,
d, J = 9Hz), 7.68 (1H, br.s).

Example 42 2- [4- (2,4-Dioxothiazolidin-5-ylmethyl) phenoxymethyl] -4-hydroxyimino-
Ethyl 2,5,7,8-tetramethylchroman-6-yloxyacetate 2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -2 according to Example 41.
5,7,8-Tetramethyl-4-oxochroman-6-
A pale yellow powdery target compound was obtained from 330 mg of ethyl oxyacetate, 170 mg of hydroxylamine hydrochloride, 170 mg of pyridine, and 3 ml of methanol.

Rf value: 0.67 (developing solvent; benzene: ethyl acetate =
1: 1) Mass spectrum (m / e): 556 (M ⁺ ) Example 43 2- [4- (2,4-Dioxothiazolidin-5-ylmethyl) phenoxymethyl] -2,5,7,8- Tetramethylchroman-6-yloxyacetic acid 2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -2,5,7,8-tetramethylchroman-6-yloxyacetic acid 2-methoxyethyl A mixture of 220 mg, 3 ml of 4N hydrogen chloride dioxane solution and 0.3 ml of water was heated under reflux for 5 hours. After completion of the reaction, the solvent was distilled off, and the obtained residue was washed with water to obtain the desired product as a pale yellow powder.

NMR spectrum (δppm, heavy acetone): 1.38 (3H, s),
1.82-2.2 (2H, nd), 2.02 (3H, s), 2.15 (6H, s), 2.65 (2H, br.
t, J = 7Hz), 3.08 (1H, dd, J = 9 and 14Hz), 3.41 (1H, dd, J
= 4 and 14Hz), 4.00 (2H, s), 4.27 (2H, s), 4.73 (1H, dd, J
= 4 and 9Hz), 6.92 (2H, d, J = 9Hz), 7.23 (2H, d, J = 9H)
z), 9.9-11.3 (1H, br., disappeared by adding heavy water).

Mass spectrum (m / e): 499 (M ⁺ ) sodium salt A sodium salt was obtained according to Example 30.

Melting point: 165-170 ° C (white powder) Example 44 2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -2,5,7,8-tetramethyl-4-oxochroman- 6-yloxyacetic acid acetic acid Following the 2-methoxyethyl ester obtained in Example 32,
The title compound was obtained as a pale yellow powder from the portion eluted with the eluent (ethyl acetate: tetrahydrofuran: methyl alcohol = 2: 2: 1).

NMR spectrum (δppm, DMSO-d ₆ ): 1.41 (3
H, s), 2.02 (3H, s), 2.18 (3H, s), 2.46 (3H, s), 2.68 (1H, d, J
= 16Hz), 2.85-3.2 (2H, nd), 3.22 (1H, dd, J = 4 and 14H
z), 4.01 (2H, s), 4.12 (2H, s), 4.61 (1H, dd, J = 4 and 9H
z), 6.87 (2H, d, J = 9Hz), 7.15 (2H, d, J = 9Hz).

Sodium salt A sodium salt was obtained according to Example 30.

Melting point: 160-165 ° C (pale yellow powder) Example 45 2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -4-hydroxyimino-
2,5,7,8-Tetramethylchroman-6-yloxyacetic acid 2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -4-hydroxyimino-
Ethyl 2,5,7,8-tetramethylchroman-6-yloxyacetate 8.9 mg, ethanol 1 ml and 0.31
A mixture of 0.2 ml of 2M aqueous sodium hydroxide solution was added to 0-5.
It was left at 19 ° C for 19 hours. After confirming disappearance of the raw materials by HPLC, 0.56 ml of 0.35% hydrochloric acid was added to the reaction mixture, and the solvent was evaporated under reduced pressure. Chloroform and water were added to the residue, and the precipitated pale yellow powder was collected by filtration and washed with water to obtain the desired product.

Mass spectrum (m / e, first atom bombardment method using glycerol as matrix (F
(Measured by AB method): [M + H] ⁺ = 529 [M−H] ⁻ = 527, so molecular weight MW = 528.

Sodium salt A sodium salt was obtained according to Example 30.

Melting point: 173-180 ° C (white powder) Application Example 13 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2,
4-Dioxothiazolidine-3-acetic acid 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2,
4-dioxothiazolidine-3-t-butyl acetate 1.0
A mixture of g and 10 ml of 4N hydrogen chloride dioxane solution was left at room temperature overnight. After completion of the reaction, the solvent was distilled off and the obtained residue was washed with water to obtain a pale yellow powdery target product.

Softening point: 85-90 ° C NMR spectrum: Signal derived from t-butyl group disappeared.

Mass spectrum (m / e): 499 (M ⁺ ) Application Example 14 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-4-oxochroman-2-ylmethoxy) benzyl] -2 , 4-Dioxothiazolidine-3-
Acetic acid According to Application Example 13, 5- [4- (6-hydroxy-
2,5,7,8-Tetramethylchroman-4-oxochroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3-t-butyl acetate 350 mg and 4N
A pale yellow powdery target product was obtained from 4 ml of a hydrogen chloride dioxane solution.

Softening point: 60-70 ° C NMR spectrum: Signal derived from t-butyl group disappeared.

Mass spectrum (m / e): 513 (M ⁺ ) Application Example 15 5- [4- (6-hydroxy-4-hydroxyimino-)
2,5,7,8-Tetramethylchroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3
-Acetic acid According to Application Example 13, 5- [4- (6-hydroxy-4)
-Hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3-t-butyl acetate 400 mg and 4N
A light brown powdery target product was obtained from 5 ml of a hydrogen chloride dioxane solution.

Softening point: 90-95 ° C. NMR spectrum: Signal derived from t-butyl group disappeared.

Application Example 16 5- [4- (6-carboxymethoxy-2,5,7,8
-Tetramethylchroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3-acetic acid 5- [4- (6-t-butoxycarbonylmethoxy-
2,5,7,8-Tetramethylchroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3
A mixture of 0.63 mg of t-butyl acetate and 6 ml of 4N hydrogen chloride in dioxane was left at room temperature overnight. After the reaction,
The product was treated according to Application Example 13 to obtain a pale yellow powdery target product.

Softening point: 95-100 ° C. NMR spectrum: Signal derived from t-butyl group disappeared.

Mass spectrum (m / e): 557 (M ⁺ ) Application Example 17 5- [4- (6-carboxymethoxy-2,5,7,8)
-Tetramethyl-4-oxochroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3-
Acetic acid According to Application Example 13, 5- [4- (6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4]
-Oxochroman-2-ylmethoxy) benzyl]-
2,4-dioxothiazolidine-3-t-butyl acetate 5
A pale yellow powdery target product was obtained from 70 mg and 6 ml of a 4N hydrogen chloride dioxane solution.

Softening point: 80-85 ° C. NMR spectrum: Signal derived from t-butyl group disappeared.

Mass spectrum (m / e): 571 (M ⁺ ) Application Example 18 5- [4- (6-Carboxymethoxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-
Ilmethoxy) benzyl] -2,4-dioxothiazolidine-3-acetic acid According to Application Example 13, 5- [4- (6-t-butoxycarbonylmethoxy-4-hydroxyimino-2,5,
7,8-Tetramethylchroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3-acetic acid t
A pale yellow powdery target product was obtained from 370 mg of -butyl and 4 ml of a 4N hydrogen chloride dioxane solution.

Softening point: 90-100 ° C. NMR spectrum: Signal derived from t-butyl group disappeared.

Application Example 19 5- [4- (6-carboxymethoxy-2,5,7,8
-Tetramethylchroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3,5-diacetic acid 5- [4- (6-t-butoxycarbonylmethoxy-
2,5,7,8-Tetramethylchroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-
A mixture of 0.41 mg of 3,5-diacetic acid di-t-butyl and 4 ml of 4N hydrogen chloride in dioxane was left at room temperature overnight. After the completion of the reaction, the reaction product was treated according to Application Example 13 to obtain a pale yellow powdery target product.

Softening point: 105-110 ° C NMR spectrum: The signal derived from t-butyl group disappeared.

Mass spectrum (m / e): 615 (M ⁺ ) Application Example 20 5- [4- (6-Carboxymethoxy-2,5,7,8)
-Tetramethyl-4-oxochroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3,
5-Diacetic acid According to Application Example 13, 5- [4- (6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4
-Oxochroman-2-ylmethoxy) benzyl]-
2,4-dioxothiazolidine-3,5-diacetic acid di-t
A pale yellow powdery target product was obtained from 340 mg of butyl and 4 ml of 4N hydrogen chloride dioxane solution.

Softening point: 105-110 ° C NMR spectrum: The signal derived from t-butyl group disappeared.

Mass spectrum (m / e): 629 (M ⁺ ) Application Example 21 5- [4- (6-Carboxymethoxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-
Ilmethoxy) benzyl] -2,4-dioxothiazolidine-3,5-diacetic acid According to Application Example 13, 5- [4- (6-t-butoxycarbonylmethoxy-4-hydroxyimino-2,5,
7,8-Tetramethylchroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3,5-di-t-butyl diacetate (270 mg) and 4N hydrogen chloride dioxane solution (3 ml) were used to obtain a pale yellow powder. I got a thing.

Softening point: 90-100 ° C. NMR spectrum: Signal derived from t-butyl group disappeared.

Example 46 2- [4- (2,4-Dioxothiazolidin-5-ylmethyl) phenoxymethyl] -2,5,7,8-tetramethylchroman-6-yloxyacetic acid ethyl a) 5- [4- ( 6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (500 mg) was dissolved in dimethylformamide (15 ml), and 55% oily sodium hydride (100 mg) was added thereto. It was stirred at room temperature for 1 hour. Then, 380 mg of ethyl bromoacetate was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into a mixture of 3N hydrochloric acid and ice and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to preparative silica gel thin layer chromatography (developing solvent; benzene: ethyl acetate = 4: 1).
The target compound was obtained.

Melting point: 104-106 ° C. Rf layer of silica gel thin layer chromatography = 0.47
(Developing solvent; benzene: ethyl acetate = 4: 1) NMR spectrum (δppm, CDCl ₃ ): 1.32 (3H, t, J
= 7Hz), 1.40 (3H, s), 1.7-2.2 (2H, nd), 2.06 (3H, s), 2.14 (3
H, s), 2.19 (3H, s), 2.62 (2H, br.t, J = 7Hz), 3.08 (1H, dd, J
= 9 and 14Hz), 3.46 (1H, dd, J = 4 and 14Hz), 3.87 and 3.97 (2H, AB type, J = 10Hz), 4.29 (2H, s), 4.30 (2H, q, J)
= 7Hz), 4.50 (1H, dd, J = and 9Hz), 6.89 (2H, d, J = 9Hz),
7.16 (2H, d, J = 9Hz), 7.8-8.8 (1H, br., Disappeared by adding heavy water).

b) 6-ethoxycarbonylmethoxy-2,5,7,8-tetramethyl-2- (4 produced according to Reference Example 40
-Nitrophenoxymethyl) chroman in Reference Examples 41 and 4
3, then according to Example 32, respectively, catalytic reduction reaction,
Diazotization and Mailbain arylation reaction, followed by thiazolidine ring formation reaction and hydrolysis reaction gave the title compound. Its melting point, Rf value by thin layer chromatography and NMR spectrum are a)
Coincided with those in.

Application Example 22 4- {5- [4- (6-hydroxy-2,5,7,8-
Ethyl tetrameethylchroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidin-3-yl} butyrate According to Application Example 1, 5- [4- (6-hydroxy-2,
5,7,8-Tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 500 m
g, ethyl gamma-bromobutyrate 1.1 g, potassium carbonate 1.
The target compound produced from 5 g and 20 ml of acetone has the following physical properties.

Rf value of silica gel thin layer chromatography = 0.56
(Developing solvent; benzene: ethyl acetate = 4: 1) NMR spectrum (δppm, CDCl ₃ ): 1.24 (3H, t, J
= 7Hz), 1.40 (3H, s), 1.7-2.4 (6H, nd), 2.10 (6H, s), 2.15 (3
H, s), 2.63 (2H, br.t, J = 7Hz), 3.05 (1H, dd, J = 9 and 14
Hz), 3.3-3.55 (1H, nd), 3.61 (2H, t, J = 7Hz), 3.85 and 3.
97 (2H, AB type, J = 10Hz), 4.12 (2H, q, J = 7Hz), 4.25 (1H, s,
(Disappeared by adding heavy water), 4.38 (1H, dd, J = 4 and 9Hz), 6.8
6 (2H, d, J = 9Hz), 7.13 (2H, d, J = 9Hz).

The derivative (W:> CH ₂ ) prepared according to Example 46a).
Or> = 0) and the derivative [W:> = NOV (V has the same meaning as described above)] produced according to Example 41 have the following physical properties.

The esters shown in Table 15 were subjected to hydrolysis according to Examples 43 and 45 or Application Example 13 to obtain the corresponding carboxylic acid derivative. They have the following physical properties.

Application Example 23 4- {5- [4- (6-hydroxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) benzyl]
-2,4-Dioxothiazolidin-3-yl} butyric acid According to Example 43, 4- {5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)) Benzyl] -2,4-dioxothiazolidin-3-yl} butyric acid ethyl ester 360 mg, acetic acid 15 ml and 3
The target compound obtained from 5 ml of N hydrochloric acid has the following physical properties.

Softening point: 57-63 ° C NMR spectrum (δppm, heavy acetone): 1.37 (3H, s),
1.6-2.4 (6H, nd), 2.03 (3H, s), 2.09 (3H, s), 2.12 (3H, s), 2.
63 (2H, br.t, J = 7Hz), 3.11 (1H, dd, J = 8 and 14Hz), 3.3
-3.55 (1H, nd), 3.58 (2H, t, J = 7Hz), 3.97 (2H, s), 4.70 (1H,
dd, J = 4 and 8Hz), 6.91 (2H, d, J = 9Hz), 7.20 (2H, d, J =
9Hz).

Example 67 2- [4- (2,4-Dioxothiazolidin-5-ylmethyl) phenoxymethyl] -2,5,7,8-tetramethylchroman-6-yloxyacetamide According to Example 46a), 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 2
g, 555 oily sodium hydride 0.4 g, iodoacetamide 0.84 g, and dimethylformamide 25
The target compound produced from ml has the following physical properties.

Softening point: 152-157 ° C. Rf value of silica gel thin layer chromatography = 0.19
((Developing solvent; benzene: ethyl acetate = 1: 1) NMR spectrum (δ ppm, DMSO-d ₆ ): 1.32 (3
H, s), 1.7-2.1 (2H, nd), 1.97 (3H, s), 2.09 (6H, s), 2.4-2.7
(2H, m), 3.02 (1H, dd, J = 8 and 15Hz), 3.2-3.4 (1H, nd),
3.99 (4H, s), 4.84 (1H, dd, J = 4 and 8Hz), 6.91 (2H, d, J
= 8Hz), 7.16 (2H, d, J = 8Hz), 7.3-7.7 (2H, br.).

Example 68 5- [4- (2,5,7,8-Tetramethyl-6-piperidinocarbonylmethoxychroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione a) 2- [4- ( 2,4-dioxothiazolidine-5-
0.5 g of ethyl dimethyl) phenoxymethyl] -2,5,7,8-tetramethylchroman-6-yloxyacetate
A mixture of and 2 ml of piperidine was heated at 80 ° C. for 3 hours.
The reaction mixture was poured into a mixture of 3N hydrochloric acid and ice and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent: benzene:
It was attached to ethyl acetate = 3: 2) to obtain the target compound.

Softening point: 83-90 ° C. Rf value of Shikagel thin layer chromatography = 0.62
(Developing solvent; benzene: ethyl acetate = 2: 3) NMR spectrum (δ ppm, heavy acetone): 1.3-1.8 (6H,
m), 1.39 (3H, s), 1.8-2.2 (2H, nd), 2.01 (3H, s), 2.12 (3H,
s), 2.14 (3H, s), 2.64 (2H, br.t, J = 7Hz), 3.08 (1H, dd, J =
9 and 15Hz), 3.3-3.55 (1H, nd), 3.4-3.8 (4H, m), 3.99 (2
H, s), 4.34 (2H, s), 4.73 (1H, dd, J = 4 and 9Hz), 6.91 (2
H, d, J = 8Hz), 7.21 (2H, d, J = 8Hz).

Mass spectrum (m / e): 566 (M ⁺ ) b) 2- [4- (2,4-dioxothiazolidine-5-
Ilmethyl) phenoxymethyl] -2,5,7,8-tetramethylchroman-6-yloxyacetic acid 500 mg, piperidine 85 mg, triethylamine 243 mg, iodide 2-
A mixture of 307 mg of chloro-1-methylpyridinium and 7 ml of dioxane was heated at 40 ° C. for 3 hours. The reaction mixture was acidified with 5% hydrochloric acid and extracted with ethyl acetate.
The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 3: 2) to obtain the target compound. The compound obtained in a) had the same Rf value, mass spectrum, and NMR spectrum data as obtained by silica gel thin layer chromatography.

Example 69 5- [4- (6-morpholinocarbonylmethoxy-2,
5,7,8-Tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione In accordance with Example 68b), 2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxy. Methyl]
The target compound prepared from -2,5,7,8-tetramethylchroman-6-yloxyacetic acid 500 mg, morpholine 87 mg, triethylamine 243 mg, 2-chloro-1-methylpyridinium iodide 307 mg, and dioxane 5 ml had the following physical properties. Have.

Rf value of silica gel thin layer chromatography = 0.41
(Developing solvent; benzene: ethyl acetate = 2: 3) NMR spectrum (δ ppm, heavy acetone): 1.40 (3H, s),
1.75-2.2 (2H, nd), 2.03 (3H, s), 2.14 (6H, s), 2.65 (2H, br.
t, J = 6Hz), 3.08 (1H, dd, J = 9 and 15Hz), 3.43 (1H, dd, J
= 4 and 15Hz), 3.63 (8H, s), 4.00 (2H, s), 4.38 (2H, s),
4.73 (1H, dd, J = 4 and 9Hz), 6.92 (2H, d, J = 9Hz), 7.22
(2H, d, J = 9Hz).

Reference Example 1 (C-4) Ethyl 6-hydroxy-5,7,8-trimethylchroman-2-carboxylate Ethyl 6-hydroxy-5,7,8-trimethylchromone-2-carboxylate 14 g was dissolved in 320 ml of acetic acid. In the presence of 3.5 g of 10% palladium carbon, catalytic reduction was carried out at a hydrogen pressure of 3 atm at 60 to 65 ° C for 1 hour. The catalyst was filtered off, the filtrate was poured into water and the precipitated white crystals were collected by filtration. The melting point of this object was 108-109 ° C.

NMR spectrum (δppm, CDCl ₃ ): 1.28 (3H, t, J
= 7Hz), 2.07 (3H, s), 2.17 (6H, 3), 1.9-2.3 (2H, nd), 2.65 (2
H, br.t, J = 7Hz), 4.22 (2H, q, J = 7Hz), 4.1-4.3 (1H, nd), 4.
60 (1H, dd, J = 7 and 4Hz).

Reference Example 2 (C-5) Ethyl 6-methoxymethoxy-5,7,8-trimethylchroman-2-carboxylate Ethyl 6-hydroxy-5,7,8, -trimethylchroman-2-carboxylate 14.3 g, To a mixture of 130 ml of dimethylformamide, under a nitrogen stream, 5-10
At 0 ° C., 3 g of 55% oily sodium hydride (wash twice with scrohexane) are added in small portions. After stirring at room temperature for 1 hour, the mixture was ice-cooled to 3 to 5 ° C, and chloromethyl ether was added.
6 g are added dropwise. After the dropping, stir for 1 hour at room temperature.
The reaction mixture is poured into ice water and extracted with black hexane. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 25.1).
And the target compound was obtained.

Rf value of silica gel thin layer chromatography = 0.41
(Developing solvent; benzene: ethyl acetate = 20: 1) NMR spectrum (δppm, CDCl ₃ ): 1.27 (3H, t, J
= 7Hz) 2.0-2.4 (2H, nd), 2.15 (3H, s), 2.16 (3H, s), 2.20 (3
H, s), 2.64 (2H, br.t, J = 7Hz), 3.61 (3H, s), 4.24 (2H, q, J =
7Hz), 4.64 (1H, dd, J = 4 and 7Hz), 4.87 (2H, s).

Reference Example 3 (C-6) Ethyl 6-methoxymethoxy-5,7,8-trimethyl-2-octylchroman-2-carboxylate 2 g of diisopropylamine and 80 ml of tetrahydrofuran
Under a nitrogen stream at −60 to −50 ° C., a hexane solution of n-butyllithium (n-butyllithium 1.
6.8 ml (62 mmol / ml) was added dropwise, and the mixture was allowed to stand at room temperature for 10 minutes. Next, 4 g of ethyl 6-methoxymethoxy-5,7,8-trimethylchroman-2-carboxylate was dissolved in about 10 ml of tetrahydrofuran at -60 ° C, and the mixture was stirred for 1 hour. Then, 5 g of octyl bromide was dissolved in about 20 ml of tetrahydrofuran and stirred at -60 ° C for 1 hour, at room temperature for 1 hour, and further heated at 50 ° C for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: benzene) to obtain the target compound.

Rf value of silica gel thin layer chromatography; 0.58
(Developing solvent; benzene: ethyl acetate = 20: 1) NMR spectrum (δ ppm, CDCl ₃ ): 0.89 (3H, br.
t, J = 6Hz), 1.15 (3H, t, J = 7Hz), 1.2-1.6 (12H, m), 1.6-2.4
(4H, m), 2.1 (3H, s), 2.18 (3H, s), 2.2 (3H, s), 2.4-2.7 (2H,
m), 3.59 (2H, s), 4.11 (2H, q, J = 7Hz), 4.85 (2H, s).

Reference Example 4 (A-1 ′) 6-methoxymethoxy-5,7,8-trimethyl-2-
Octyl chroman-2-ylmethanol Lithium Aluminium Hydride 0.45 g and tetrahydrofuran 30 ml were added to a mixture of ethyl 6 under a nitrogen stream.
3.3 g of -methoxymethoxy-5,7,8-trimethyl-2-octylchroman-2-carboxylate was dissolved in 10 ml of tetrahydrofuran, added dropwise under ice cooling, and then stirred at room temperature for 3 hours. Ethyl acetate and 5% hydrochloric acid were added to the reaction mixture under ice cooling, the organic layer was separated, and the aqueous layer was further extracted with ethyl acetate. Both extracts were combined, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound having an Rf value of 0.45 in silica gel thin layer chromatography (developing solvent; benzene: ethyl acetate = 10: 1).

NMR spectrum (δppm, CDCl ₃ ): 0.7-1.0 (3H,
m), 1.0-2.3 (16H, m), 2.10 (3H, s), 2.15 (3H, s), 2.20 (3H,
s), 2.59 (2H, br.t, J = 7Hz), 3.6 (5H, s), 4.87 (2H, s).

Reference Example 5 (A-2) 6-methoxymethoxy-5,7,8-trimethyl-2-
(4-Nitrophenoxymethyl) -2-octylchroman 6-methoxymethoxy-5,7,8-trimethyl-2-
55 g of a mixture of 3 g of oxochroman-2-ylmethanol and 25 ml of dimethylformamide at room temperature under a nitrogen stream.
% Oily sodium hydride 0.38 g, then 50
Heated at ° C for 2 hours. A mixture of 1.4 g of p-chloronitrobenzene and 2 ml of benzene was added dropwise under ice cooling, and the mixture was heated at 50 ° C. for 2 hours. The reaction mixture was poured into ice water and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (eluent: benzene) to obtain the target compound.

Rf value of silica gel thin layer chromatography = 0.46
(Developing solvent; benzene) NMR spectrum (δppm, CDCl ₃ ): 0.7-1.0 (3H,
m), 1.0-1.9 (14H, m), 1.9-2.3 (2H, nd), 2.06 (3H, s), 2.15 (3
H, s), 2.19 (3H, s), 2.6 (2H, br.t, J = 7Hz), 3.60 (3H, s), 4.0
5 (2H, s), 4.87 (2H, s), 6.97 (2H, d, J = 9Hz), 8.18 (2H, d, J =
9Hz).

Reference Example 6 (A-3-deprotection step) 6-hydroxy-5,7,8-trimethyl-2- (4-
Nitrophenoxymethyl) -2-octylchroman 6-methoxymethoxy-5,7,8-trimethyl-2-
(4-nitrophenoxymethyl) -2-octylchroman 3.7 g, acetic acid 10 ml, benzene 30 ml and 10%
A mixture of 0.75 ml of sulfuric acid was heated to reflux for 30 minutes. Pour the reaction mixture into water and extract with benzene, wash the extract with water,
It was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound having an Rf value of 0.34 in silica gel thin layer chromatography (developing solvent: benzene).

NMR spectrum (δppm, CDCl ₃ ): 0.7-1.0 (3H,
m), 1.0-1.85 (14H, m), 1.85-2.2 (2H, nd), 2.10 (6H, s), 2.16
(3H, s), 2.63 (2H, br.t, J = 7Hz), 4.06 (2H, s), 4.19 (1H, s,
Disappeared by addition of heavy water), 6.97 (2H, d, J = 9Hz), 8.19 (2H, d, J = 9H)
z).

Reference Example 7 (A-3-acylated) 6-acetoxy-5,7,8-trimethyl-2- (4-
Nitrophenoxymethyl) -2-octylchroman 6-hydroxy-5,7,8-trimethyl-2- (4-
2. Nitrophenoxymethyl) -2-octylchroman 3.
1.2 g of acetic anhydride was added to a mixture of 5 g, 10 ml of pyridine and 10 ml of benzene, and the mixture was stirred at room temperature for 2 hours. Pour the reaction mixture into water and extract with benzene.
It was washed with hydrochloric acid and then with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and Rf value in silica gel thin layer chromatography (developing solvent; benzene) = 0.
4 target compound was obtained.

NMR spectrum (δppm, CDCl ₃ ): 0.75-1.0 (3
H, m), 1.1-1.65 (12H, m), 1.65-2.15 (4H, nd), 1.99 (3H, s),
2.04 (3H, s), 2.08 (3H, s), 2.32 (3H, s), 2.63 (2H, br.t, J = 7
Hz), 4.07 (2H, s), 6.98 (2H, d, J = 9Hz), 8.20 (2H, d, J = 9H
z).

Reference Example _{8 (A-3-H 2} ) 6- acetoxy-2- (4-amino-phenoxymethyl)
-5,7,8-Trimethyl-2-octylchroman 6-acetoxy-5,7,8-trimethyl-2- (4-
Nitrophenoxymethyl) -2-octylchroman 4
g, 10% palladium carbon 0.8g, methanol 30m
A mixture of 1 ml of benzene and 10 ml of benzene was shaken for 5 hours under a hydrogen pressure of 3-5 atm using a Parr hydrogenator. The palladium carbon was filtered off, the filtrate was concentrated under reduced pressure, and the obtained crystals were washed with hexane to obtain the desired product.

Melting point: 112-114 ° C. NMR spectrum (δ ppm, CDCl ₃ ): 0.7-1.05 (3
H, m), 1.05-1.65 (12H, m), 1.65-2.2 (4H, nd), 1.97 (3H, s),
2.02 (3H, s), 2.10 (3H, s), 2.31 (3H, s), 2.59 (2H, br.t, J = 7
Hz), 3.0-3.7 (2H, br.s, disappears by adding heavy water), 3.86 (2H,
s), 6.62 (2H, d, J = 10Hz), 6.75 (2H, d, J = 10Hz).

Reference Example 9 (A-4) Ethyl 3- [4- (6-acetoxy-5,7,8-trimethyl-2-octylchroman-2-ylmethoxy)
Phenyl] -2-chloropropionate 6-acetoxy-2- (4-aminophenoxymethyl)
-5,7,8-Trimethyl-2-octylchroman 3.
In a mixture of 2 g and 35 ml of acetone, under a nitrogen stream, 5-1
Concentrated hydrochloric acid 3.5 ml at 0 ° C, then sodium nitrite 0.61
g was dissolved in 1.7 ml of water and added dropwise, and further 7.2 ml of ethyl acrylate was added dropwise. The internal temperature is adjusted to 40 to 43 ° C., and 0.1 g of cuprous oxide is gradually added. Generation of nitrogen is completed in about 30 minutes. The reaction mixture was poured into water and extracted with benzene.
The extract was washed with water, dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; cyclohexane: ethyl acetate = 10: 1) to obtain the target compound.

Rf value of silica gel thin layer chromatography = 0.27
(Developing solvent; cyclohexane: ethyl acetate = 9: 1) NMR spectrum (δ ppm, CDCl ₃ ): 0.8-1.05 (3
H, m), 1.05-1.65 (15H, m), 1.65-2.2 (4H, nd), 1.97 (3H, s),
2.03 (3H, s), 2.09 (3H, s), 2.30 (3H, s), 2.6 (2H, br.t, J = 7H
z), 3.07 (1H, dd.J = 7 and 14Hz), 3.30 (1H, dd, J = 7 and 14Hz), 3.92 (2H, s), 4.18 (2H, q, J = 7Hz), 4.36 (1H , t, J ＝
7Hz), 6.85 (2H, d, J = 9Hz), 7.13 (2H, d, J = 9Hz).

Reference Example 10 (D-1) 6-acetoxy-2-methyl-2- (4-nitrophenoxymethyl) -4-oxo-7- (1,1,3,3-tetramethylbutyl) chroman 5-acetoxy- 2-hydroxy-4- (1,1,3,
3-tetramethylbutyl) acetophenone 23 g, 1-
(4-Nitrophenoxy) -2-propanone 14.7
A mixture of g, 8 g of pyrrolidine and 300 ml of benzene is stirred at room temperature for 3 hours. Then, the mixture was heated under reflux for 10 hours.
The reaction mixture was poured into ice water and extracted with benzene. The extract was washed with 5% hydrochloric acid and then with water, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, 15 g of acetic anhydride and 400 ml of pyridine were added to the residue, and the mixture was left at room temperature for 1 day.
The reaction mixture was poured into ice water and extracted with benzene. The extract was washed with 5% hydrochloric acid and then with water, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 20: 1), and further recrystallized from methanol to obtain the target compound.

Melting point: 165.5-167 ° C NMR spectrum (δppm, CDCl ₃ ): 0.76 (9H, s),
1.36 (6H, s), 1.57 (3H, s), 1.83 (2H, s), 2.32 (3H, s), 2.74 (1
H, d, J = 17Hz), 3.10 (1H, d, J = 17Hz), 4.11 and 4.24 (2H,
AB type, J = 9Hz), 6.95 (2H, d, J = 9Hz), 6.98 (1H, s), 7.50 (1H,
s), 8.20 (2H, d, J = 9Hz).

Reference Example 11 (D-2) 6-acetoxy-2- (4-aminophenoxymethyl)
2-Methyl-4-oxo-7- (1,1,3,3-tetramethylbutyl) chroman 6-acetoxy-2-methyl-2- (4-nitrophenoxymethyl) -4-oxo-7- ( 12.3 g of 1,1,3,3-tetramethylbutyl) chroman was dissolved in a mixture of 200 ml of methanol and 20 ml of benzene, and 10
% Palladium carbon in the presence of 2.4 g at a hydrogen pressure of about 1 atm for 6 hours at room temperature. The palladium carbon was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate =).
4: 1) to obtain the target compound.

Rf value of silica gel thin layer chromatography = 0.29
(Developing solvent; benzene: ethyl acetate = 4: 1) NMR spectrum (δppm, CDCl ₃ ): 0.78 (9H, s),
1.37 (6H, s), 1.52 (3H, s), 1.83 (2H, s), 2.30 (3H, s), 2.66 (1
H, d, J = 17Hz), 3.10 (1H, d, J = 17Hz), 3.4 (2H, br.s, disappeared by adding heavy water), 3.92 and 4.06 (2H, AB type, J = 9Hz), 6.58 ( 2H,
d, J = 9Hz), 6.76 (2H, d, J = 9Hz), 7.00 (1H, s), 7.50 (1H,
s).

Reference Example 12 (D-3) Ethyl 3- [4- (6-acetoxy-2-methyl-4]
-Oxo-7- (1,1,3,3-tetramethylbutyl) chroman-2-ylmethoxy] phenyl] -2-chloropropionate According to Reference Example 9, 6-acetoxy-2- (4-amino) Phenoxymethyl) -2-methyl-4-oxo-7-
(1,1,3,3-tetramethylbutyl) chroman 9
g, sodium nitrite 1.8 g, concentrated hydrochloric acid 10 ml, ethyl acrylate 20 g, cuprous oxide 0.3 g, acetone 10
The target product produced from 0 ml and about 8 ml of water has the following physical properties.

Rf value of silica gel thin layer chromatography = 0.32
(Developing solvent; benzene: ethyl acetate = 20: 1) NMR spectrum (δ ppm, CDCl ₃ ): 0.78 (9H, s),
1.23 (3H, t, J = 7Hz), 1.38 (6H, s), 1.53 (3H, s), 1.85 (2H,
s), 2.30 (3H, s), 2.69 (1H, d, J = 17Hz), 3.08 (1H, dd, J = 7.5
And 15Hz), 3.10 (1H, d, J = 17Hz), 3.32 (1H, dd, J = 7.5 and 15Hz), 3.99 and 4.12 (2H, AB type, J = 10.5Hz), 4.18 (2
H, q, J = 7Hz), 4.36 (2H, t, J = 7Hz), 6.82 (2H, d, J = 9Hz), 7.
01 (1H, s), 7.16 (2H, d, J = 9Hz), 7.52 (1H, s).

Reference Example 13 (F-1) 6-acetoxy-4-hydroxy-2-methyl-2-
(4-Nitrophenoxymethyl) -7- (1,1,3,
3-Tetramethylbutyl) chroman 6-acetoxy-2-methyl-2- (4-nitrophenoxymethyl) -4-oxo-7- (1,1,3,3-tetramethylbutyl) chroman 13 g was added to methanol 100
It was dissolved in a mixed solvent of 10 ml of benzene and 10 ml of benzene, 1 g of sodium borohydride was added under ice cooling, and the mixture was stirred for 30 minutes under ice cooling. The reaction mixture was poured into ice water, neutralized with 10% hydrochloric acid, extracted with benzene, the extract was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 4: 1) to obtain the target compound.

Rf value of silica gel thin layer chromatography = 0.32
(Developing solvent; benzene: ethyl acetate = 4: 1) NMR spectrum (δppm, CDCl ₃ ): 0.77 (9H, s),
1.34 (6H, s), 1.54 (3H, s), 1.80 (2H, s), 1.85-2.25 (1H, nd),
2.29 (3H, s), 2.48 (1H, dd, J = 7 and 14Hz), 4.02 (2H, AB
Type, J = 12Hz), 4.7-5.0 (1H, m), 6.85 (1H, s), 6.95 (2H, d, J =
9Hz), 7.08 (1H, s), 8.18 (2H, d, J = 9Hz).

Reference Example 14 (F-3) 6-hydroxy-2-methyl-2- (4-nitrophenoxymethyl) -7- (1,1,3,3-tetramethylbutyl) -2H-chromene) (1) and , 6-acetoxy-2-methyl-2- (4-nitrophenoxymethyl) -7- (1,1,3,3-tetramethylbutyl) -2H-chromene (2) 6-acetoxy-4-hydroxy-2 -Methyl-2-
(4-Nitrophenoxymethyl) -7- (1,1,3,
10.2 g of 3-tetramethylbutyl) chroman and 0.4 g of p-toluenesulfonic acid were dissolved in 200 ml of benzene and heated under reflux for 30 minutes under a nitrogen stream. The reaction mixture was poured into ice water and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: benzene), and Rf in silica gel thin layer chromatography (developing solvent: benzene: ethyl acetate = 20: 1).
Target compound (1) having a value of 0.53 and Rf value of 0.50
The target compound (2) of was obtained.

NMR spectrum of (1) (δ ppm, CDCl ₃ ): 0.7
5 (9H, s), 1.38 (6H, s), 1.56 (3H, s), 1.89 (2H, s), 4.09 (2H,
s), 4.43 (1H, s, disappears when heavy water is added), 5.63 (1H, d, J = 10Hz), 6.
32 (1H, s), 6.41 (1H, d, J = 10Hz), 6.73 (1H, s), 6.96 (2H, d, J
= 9Hz), 8.20 (2H, d, J = 9Hz).

NMR spectrum of (2) (δ ppm, CDCl ₃ ): 0.7
6 (9H, s), 1.32 (6H, s), 1.58 (3H, s), 1.79 (2H, s), 2.29 (3H,
s), 4.10 (2H, s), 5.62 (1H, d, J = 10Hz), 6.43 (1H, d, J = 10H
z), 6.69 (1H, s), 6.79 (1H, s), 6.93 (2H, d, J = 9Hz), 8.18 (2
H, d, J = 9Hz).

Reference Example 15 (F-5) 6-acetoxy-2- (4-aminophenoxymethyl)
2-Methyl-7- (1,1,3,3-tetramethylbutyl) chroman 6-acetoxy-2-methyl-2- (4-nitrophenoxymethyl) -7- (1,1,3,3- A mixture of 9.1 g of (tetramethylbutyl), -2H-chromene, 2 g of 10% palladium carbon and 150 ml of methanol was shaken for 10 hours at 3-5 atm under hydrogen pressure using a Parr hydrogenation device. The palladium carbon was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 10: 1) to obtain the target compound.

Rf value of silica gel thin layer chromatography = 0.27
(Developing solvent; benzene: ethyl acetate = 9: 1) NMR spectrum (δppm, CDCl ₃ ): 0.77 (9H, s),
1.34 (6H, s), 1.42 (3H, s), 1.7-2.2 (2H, nd), 1.78 (2H, s), 2.
27 (3H, s), 2.65 (2H, br.q, J = 7Hz), 3.36 (2H, br, s, disappeared by adding heavy water), 3.85 (2H, AB type, J = 9Hz), 6.54-6.88 ( 6H, m).

Reference Example 16 (A-4) Ethyl 3- [4- [6-acetoxy-2-methyl-7]
-(1,1,3,3-tetramethylbutyl) chroman-
2-ylmethoxy] phenyl] -2-chloropropionate According to Reference Example 9, 6-acetoxy-2- (4-aminophenoxymethyl) -2-methyl-7- (1,1,3,3)
3-Tetramethylbutyl) chroman 7.9 g, sodium nitrite 1.6 g, concentrated hydrochloric acid 9 ml, ethyl acrylate 18
g, cuprous oxide 260 mg, acetone 90 ml and water about 5
The target product produced from ml has the following physical properties.

Rf value of silica gel thin layer chromatography = 0.55
(Developing solvent; benzene: ethyl acetate = 20: 1) NMR spectrum (δ ppm, CDCl ₃ ): 0.78 (9H, s),
1.22 (3H, t, J = 7Hz), 1.35 (6H, s), 1.43 (3H, s), 1.7-2.3 (2
H, nd), 1.79 (2H, s), 2.27 (3H, s), 2.70 (2H, br.t, J = 6Hz),
3.07 (1H, dd, J = 7.5 and 15Hz), 3.32 (1H, dd, J = 7.5 and 15Hz), 3.91 (2H, AB type, J = 9Hz), 4.18 (2H, q, J = 7Hz), 4.3
7 (1H, t, J = 7Hz), 6.72 (1H, s), 6.85 (1H, s), 6.86 (2H, d, J =
9Hz), 7.16 (2H, d, J = 9Hz).

Reference Example 17 (E-1) Ethyl 6-hydroxy-5,7,8-trimethyl-4
-Oxochroman-2-carboxylate Ethyl 6-hydroxy-5,7,8-trimethylchromone-2-carboxylate 12 g was dissolved in 250 ml of dimethylformamide and dissolved in the presence of 16 g of 10% palladium on carbon at a hydrogen pressure of 5 atm, 50-60. Catalytic reduction was carried out at ℃ for 7 hours. The catalyst was filtered off, the filtrate was poured into a large amount of water, and the precipitated crystals were collected by filtration. The obtained crystal was recrystallized from ethyl acetate to obtain the target compound.

Melting point: 120-121 ° C NMR spectrum (δppm, CDCl ₃ ): 1.26 (3H, t, J
= 7Hz), 2.23 (6H, s), 2.52 (3H, s), 2.98 (2H, d, J = 7Hz), 4.2
4 (2H, q, J = 7Hz), 4.83 (1H, s), 4.94 (1H, t, J = 7Hz).

The filtrate obtained by filtering the target compound was extracted with ethyl acetate,
The extract is dried over anhydrous sodium sulfate, then the solvent is distilled off,
The residue is subjected to silica gel column chromatography (eluent;
Hexane: ethyl acetate = 1: 1), and the target compound was extracted from the first fraction and ethyl 4,6-dihydroxy-5,7,8-trimethylchroman-2-carboxylate was extracted from the second fraction. Obtained.

Melting point: 138-144 [deg.] C. Reference Example 18 (E-2) Ethylspiro [6-hydroxy-5,7,8-trimethylchroman-4,2 '-[1,3] dithiane] -2-
Carboxylate ethyl 6-hydroxy-5,7,8-trimethyl-4
-Oxochroman-2-carboxylate 16.6 g,
1,3-Propanedithiol 9.7 g of chloroform 5
20 ml of boron trifluoride-acetic acid complex salt (boron trifluoride: 40%) was added dropwise to the 00 ml solution under ice cooling, and the mixture was allowed to stand at room temperature for 24 hours. The reaction mixture was poured into ice water, neutralized with potassium carbonate, extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain the target compound.

Mp: 186-188 ° C. NMR spectrum _{(δppm, CDCl 3): 1.35} (3H, t, J
= 7Hz), 1.8-2.4 (2H, nd), 2.18 (6H, s), 2.5-2.9 (3H, nd), 2.
80 (3H, s), 3.0-3.5 (3H, m), 4.31 (2H, q, J = 7Hz), 4.50 (1H,
s), 4.79 (1H, dd, J = 2 and 10Hz).

Reference Example 19 (E-3) Ethyl Spiro [6-methoxymethoxy-5,7,8-
Trimethylchroman-4,2 '-[1,3] dithiane]
-2-carboxylate ethyl spiro [6-hydroxy-5,7,8-trimethylchroman-4,2 '-[1,3] dithiane] -2-
Carboxylate 6.6 g, dimethylformamide 10
A mixture of 0 ml and 55% sodium hydride (1 g) was sonicated at room temperature for 1 hour, chloromethyl methyl ether (3 g) was added under ice cooling, and the mixture was left at room temperature overnight. Water was added to the reaction mixture and extracted with ethyl acetate, and the aqueous layer was further extracted with benzene. Both the ethyl acetate solution and the benzene solution were washed with water three times, and both were combined and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 5: 1) to obtain the target compound.

Rf value of silica gel thin layer chromatography = 0.21
(Developing solvent; hexane: ethyl acetate = 5: 1) NMR spectrum (δppm, CDCl ₃ ): 1.34 (3H, t, J
= 7Hz), 1.7-2.4 (2H, nd), 2.16 (3H, s), 2.21 (3H, s), 2.5-3.
0 (3H, nd), 2.87 (3H, s), 3.0-3.5 (3H, nd), 3.60 (3H, s), 4.30
(2H, q, J = 7Hz), 4.7-5.0 (1H, nd), 4.89 (2H, s).

Reference Example 20 (E-4) Ethyl Spiro [2- (3,7-dimethyloctyl)-
6-Methoxymethoxy-5,7,8-trimethylchroman-4,2 '-[1,3] dithiane] -2-carboxylate In a nitrogen atmosphere, in a solution of 2.9 g of diisopropylamine in 30 ml of tetrahydrofuran, -60 ° C- At -50 ° C, n
17.7 ml of a hexane solution of -butyllithium (1.62 mmol / ml of n-butyllithium) was added dropwise to the mixture at room temperature for 10
Let stand for a minute. Then, at -60 ° C, ethyl spiro [6-
Methoxymethoxy-5,7,8-trimethylchroman-
6 g of 4,2 '-[1,3] dithiane] -2-carboxylate was dissolved in 10 ml of tetrahydrofuran and added dropwise. After stirring for 1 hour, 6.4 g of 3,7-dimethyloctyl bromide was dissolved in 5 ml of tetrahydrofuran, added dropwise, and stirred for 1 hour. Then at room temperature for 1 hour, 45-50
The mixture was stirred at ℃ for 1.5 hours and left at room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 10: 1).
To give the target compound (pale yellow oil).

Rf value of silica gel thin layer chromatography = 0.57
(Developing solvent; benzene: ethyl acetate = 20: 1) NMR spectrum (δppm, CDCl ₃ ): 0.87 (9H, d, J
= 7Hz), 1.0-2.3 (14H, m), 1.17 (3H, t, J = 7Hz), 2.17 (3H,
s), 2.21 (3H, s), 2.3-2.9 (2H, nd), 2.62 (1H, d, J = 14Hz), 2.
83 (3H, s), 2.97-3.5 (2H, m), 3.59 (3H, s), 3.73 (1H, d, J = 14
Hz), 4.03 (1H, q, J = 7Hz), 4.07 (1H, q, J = 7Hz), 4.88 (2H,
s).

Reference Example 21 (E-5) Spiro [2- (3,7-dimethyloctyl) -6-methoxymethoxy-5,7,8-trimethylchroman-4,
2 '-[1,3] dithian] -2-ylmethanol ethyl spiro [2- (3,7-dimethyloctyl)-
4 g of 6-methoxymethoxy-5,7,8-trimethylchroman-4,2 '-[1,3] dithiane] -2-carboxylate was dissolved in 20 ml of tetrahydrofuran, and in a mixture of 0.41 g of lithium aluminum hydride and 30 ml of tetrahydrofuran. Then, the mixture was added dropwise under nitrogen cooling in a nitrogen stream and stirred at room temperature for 3 hours. About 10 ml of ethyl acetate and about 30 ml of 5% hydrochloric acid were added to the reaction mixture under ice cooling, the organic layer was separated, and the aqueous layer was further extracted with ethyl acetate. Both extracts were combined, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and silica gel thin layer chromatography (developing solvent; benzene: ethyl acetate = 20:
The target compound was obtained as an Rf value in 1) = 0.36, a pale yellow oil.

NMR spectrum (δppm, CDCl ₃ ): 0.87 (9H, d, J
= 7Hz), 1.0-2.0 (12H, m), 2.0-2.5 (2H, nd), 2.08 (3H, s), 2.
20 (3H, s), 2.34 (1H, br.s, disappeared by adding heavy water), 2.5-3.0 (3H,
m), 2.92 (3H, s), 3.0-3.6 (4H, m), 3.61 (3H, s), 3.76 (1H, dd,
J = 6 and 12 Hz), 4.89 (2H, s).

Reference Example 22 (E-6) Spiro [2- (3,7-dimethyloctyl) -6-methoxymethoxy-5,7,8-trimethyl-2- (4-nitrophenoxymethyl) chroman 4,2 '-[ 1, 3]
Dithiane] Spiro [2- (3,7-dimethyloctyl) -6-methoxymethoxy-5,7,8-trimethylchroman-4,
2 '-[1,3] dithian] -2-ylmethanol 3.
To a mixture of 6 g and 30 ml of dimethylformamide, 0.46 g of 55% oily sodium hydride was added at room temperature in a nitrogen stream and then heated at 50 ° C. for 2 hours. A mixture of 1.66 g of p-chloronitrobenzene and 3 ml of benzene was added dropwise under ice cooling, and then the mixture was heated at 50 ° C. for 2 hours. The reaction mixture was poured into water and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure,
The residue is subjected to silica gel column chromatography (eluent;
Subjected to benzene: ethyl acetate = 50: 1) to obtain the target compound.

Rf value of silica gel thin layer chromatography = 0.55
(Developing solvent; benzene: ethyl acetate = 20: 1) NMR spectrum (δppm, CDCl ₃ ): 0.87 (9H, d, J
= 7Hz), 1.0-2.3 (14H, m), 2.08 (3H, s), 2.21 (3H, s), 2.3-3.
0 (3H, m), 2.89 (3H, s), 3.0-3.6 (3H, m), 3.61 (3H, s), 3.99 (1
H, d, J = 9Hz), 4.45 (1H, d, J = 9Hz), 4.89 (2H, s), 6.92 (2H,
d, J = 9Hz), 8.17 (2H, d, J = 9Hz).

Reference Example 23 (E-7) and (A-3 deprotection) 2- (3,7-dimethyloctyl) -6-hydroxy-
5,7,8-Trimethyl-2- (4-nitrophenoxymethyl) -4-oxochroman spiro [2- (3,7-dimethyloctyl) -6-methoxymethoxy-5,7,8-trimethyl-2- ( 4-nitrophenoxymethyl) chroman-4,2 '-[1,
3) Dithiane) (3.4 g), mercuric chloride (2.2 g), mercuric oxide (1.7 g), tetrahydrofuran (10 ml), methanol (27 ml) and water (3 ml) were heated under reflux for 2 hours. Benzene was added to the reaction mixture, the insoluble material was filtered off, the filtrate was washed with an aqueous solution of ammonium sulfate and then with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, 30 ml of benzene, 10 ml of acetic acid and 0.5 ml of 10% sulfuric acid aqueous solution were added to the residue, and the mixture was refluxed for 30 minutes. The reaction mixture was poured into water and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: benzene: ethyl acetate = 100: 3), and the obtained crystals were recrystallized from a mixed solution of benzene and hexane to give the target compound. Got

Mp: 121-123 ° C. NMR spectrum _{(δppm, CDCl 3): 0.85} (9H, d, J
= 7Hz), 1.0-1.7 (10H, m), 1.7-2.1 (2H, m), 2.11 (3H, s), 2.2
1 (3H, s), 2.55 (3H, s), 2.76 and 2.98 (2H, AB type, J = 16H
z), 4.16 (2H, s), 4.57 (1H, s, disappeared by adding heavy water), 7.96 (2H, d,
J = 9Hz), 8.20 (2H, d, J = 9Hz).

Reference Example 24 (A-3-acylated) 6-acetoxy-2- (3,7-dimethyloctyl)-
5,7,8-Trimethyl-2- (4-nitrophenoxymethyl) -4-oxochroman According to Reference Example 7, 2- (3,7-dimethyloctyl)
-6-hydroxy-5,7,8-trimethyl-2- (4
-Nitrophenoxymethyl) -4-oxochroman 1.
The target compound produced from 8 g, acetic anhydride 0.5 g, pyridine 5 ml, and benzene 10 ml has the following physical properties.

Rf value of silica gel thin layer chromatography = 0.41
(Developing solvent; benzene: ethyl acetate = 20: 1) NMR spectrum (δppm, CDCl ₃ ): 0.85 (9H, d, J
= 7Hz), 1.0-2.0 (12H, m), 2.08 (3H, s), 2.11 (3H, s), 2.33 (3
H, s), 2.41 (3H, s), 2.80 and 3.00 (2H, AB type, J = 16Hz), 4.
17 (2H, s), 6.95 (2H, d, J = 9Hz), 8.20 (2H, d, J = 9Hz).

Reference Example 25 (D-2) 6-acetoxy-2- (4-aminophenoxymethyl)
-2- (3,7-Dimethyloctyl) -5,7,8-trimethyl-4-oxochroman According to Reference Example 11, 6-acetoxy-2- (3,7-
Dimethyloctyl) -5,7,8-trimethyl-2-
The target compound produced from 1.95 g of (4-nitrophenoxymethyl) -4-oxochroman and 0.4 g of 10% palladium-carbon has the following physical properties.

Rf value of silica gel thin layer chromatography = 0.31
(Developing solvent; benzene: ethyl acetate = 4: 1) NMR spectrum (δppm, CDCl ₃ ): 0.85 (9H, d, J
= 7Hz), 1.0-2.0 (12H, m), 2.09 (3H, s), 2.13 (3H, s), 2.32 (3
H, s), 2.41 (3H, s), 2.77 and 3.00 (2H, AB type, J = 16Hz), 3.
4 (2H, br.s, disappeared by adding heavy water), 3.99 (2H, s), 6.60 (2H, d, J =
9Hz), 6.70 (2H, d, J = 9Hz).

Reference Example 26 (D-3) Ethyl 3- [4- [6-acetoxy-2- (3,7-
Dimethyloctyl) -5,7,8-trimethyl-4-oxochroman-2-ylmethoxy] phenyl] -2-chloropropionate According to Reference Example 9, 6-acetoxy-2- (4-aminophenoxymethyl)- 2- (3,7-Dimethyloctyl) -5,7,8-trimethyl-4-oxochroman 1.6 g, sodium nitrite 0.28 g, concentrated hydrochloric acid 1.7.
The target compound produced from 0.1 ml of ethyl acrylate and 0.1 g of cuprous oxide has the following physical properties.

Rf value of silica gel thin layer chromatography = 0.45
(Developing solvent; benzene: ethyl acetate = 20: 1) NMR spectrum (δppm, CDCl ₃ ): 0.86 (9H, d, J
= 7Hz), 1.0-2.0 (12H, m), 1.24 (3H, t, J = 7Hz), 2.09 (3H,
s), 2.13 (3H, s), 2.33 (3H, s), 2.42 (3H, s), 2.80 and 2.98
(2H, AB type, J = 16Hz), 3.07 (1H, dd, J = 7 and 14Hz), 3,31
(1H, dd, J = 7 and 14Hz), 4,06 (2H, s), 4,18 (2H, q, J = 7H
z), 4.37 (1H, t, J = 7Hz), 6.83 (2H, d, J = 9Hz), 7.15 (2H, d, J
= 9Hz).

Reference Example 27 (D-1) 6-acetoxy-7-t-butyl-2-methyl-2-
(2-Methyl-5-nitrophenoxymethyl) -4-oxochroman According to Reference Example 10, 5-acetoxy-4-t-butyl-2-hydroxyacetophenone 4.78 g, 1- (2
The pale red foamy target substance prepared from 4.0 g of -methyl-5-nitrophenoxy) propan-2-one, 2.0 g of pyrrolidine, 50 ml of benzene, 4 ml of acetic anhydride and 50 ml of pyridine has the following physical properties.

Rf value by silica gel thin layer chromatography = 0.
24 (developing solvent; benzene: ethyl acetate = 20: 1) NMR spectrum (δ ppm, heavy acetone): 1.32 (9H, s),
1.63 (3H, s), 2.17 (3H, s), 2.32 (3H, s), 2.90 (1H, d, J = 16.5
Hz), 3.15 (1H, d, J = 16.5Hz), 4.43 (2H, AB type, J = 12Hz), 6.9
7 (1H, s), 7,38 (1H, d, J = 8Hz), 7,45 (1H, s), 7.70-7.90 (2H,
m).

Reference Example 28 (D-2) 6-acetoxy-2- (5-amino-2-methylphenoxymethyl) -7-t-butyl-2-methyl-4-oxochroman According to Reference Example 11, 6-acetoxy- Hydrogenation was performed using 7-t-butyl-2-methyl-2- (2-methyl-5-nitrophenoxymethyl) -4-oxochroman 7.3 g, 10% palladium on carbon 1 g and ethanol 100 ml to give a pale red foam. The target compound was obtained in the form of a solid.

Rf value by silica gel thin layer chromatography = 0.
13 (developing solvent; benzene: ethyl acetate = 5: 1) NMR spectrum (δ ppm, heavy acetone): 1.33 (9H, s),
1.56 (3H, s), 1.95 (3H, s), 2.31 (3H, s), 2.80 (1H, d, J = 16.5
Hz), 3.10 (1H, d, J = 16.5Hz), 4.06 (2H, s), 3.90-4.70 (2H, b
r., disappeared by addition of heavy water), 6.18 (1H, dd, J = 8 and 1.5Hz), 6,2
8 (1H, d, J = 1.5Hz), 6,78 (1H, d, J = 8Hz), 7.00 (1H, s), 7.47
(1H, s).

Reference Example 29 (D-3) Ethyl 3- [3- (6-acetoxy-7-t-butyl-2-methyl-4-oxochroman-2-ylmethoxy) -4-methylphenyl] -2-chloropropionate According to Reference Example 12, 6-acetoxy-2- (5-amino-2-methylphenoxymethyl) -7-t-butyl-
The target compound in the form of a pale yellow oil produced from 5.53 g of 2-methyl-4-oxochroman, 1.2 g of sodium nitrite, 2.4 ml of concentrated hydrochloric acid, 14 ml of ethyl acrylate, 190 mg of cuprous oxide, and 50 ml of acetone is the following. It has the following physical properties.

Rf value by silica gel thin layer chromatography = 0.
41 (developing solvent; benzene: ethyl acetate = 10: 1) NMR spectrum (δ ppm, CDCl ₃ ): 1.22 (3H, t, J
= 7.5Hz), 1.32 (9H, s), 1.57 (3H, s), 2.10 (3H, s), 2.30 (3H,
s), 2.74 (1H, d, J = 17Hz), 2.94-3.25 (1H, nd), 3.08 (1H, d, J
= 17Hz), 3.33 (1H, dd, J = 7 and 14Hz), 3.99 and 4.11
(2H, AB type, J = 10Hz), 4,18 (2H, q, J = 7.5Hz), 4,40 (1H, t, J
= 7Hz), 6.65-6.85 (2H, nd), 6.99 (1H, s), 7.07 (1H, d, J = 7.
5Hz), 7.50 (1H, s).

Reference Example 30 (A-2-Ar compound) 6-methoxymethoxy-2,5,7,8-tetramethyl-2- (5-nitropyridin-2-yloxymethyl)
Chroman 6-methoxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethanol (5.0 g) and a mixture of 20 ml of dimethylformamide were added to a mixture of 5 g of nitrogen at room temperature at room temperature.
0.96 g of 5% oily sodium hydride (washing 4 times with cyclohexane) is gradually added. After heating at 50 ° C for 10 minutes, the mixture was cooled to 10 ° C, and 4.2 g of 2-chloro-5-nitropyridine was added little by little. After standing overnight at room temperature, the reaction mixture is poured into water and extracted with benzene. The extract is washed with water and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 25: 1) to obtain the desired product.

Rf value of silica gel column chromatography = 0.5
6 (developing solvent; benzene: ethyl acetate = 10: 1) NMR spectrum (δ ppm, CDCl ₃ ): 1.40 (3H, s),
1.7-2.3 (2H, m), 2.02 (3H, s), 2.17 (6H, s), 2.65 (2H, br.t, J
= 6Hz), 3.61 (3H, s), 4.51 (2H, s), 4.88 (2H, s), 6.87 (1H, d,
J = 9Hz), 8.37 (1H, dd, J = 9 and 3Hz), 9.06 (1H, d, J = 3H
z).

Reference Example 31 (A-3-deprotection step) 6-hydroxy-2,5,7,8-tetramethyl-2-
(5-Nitropyridin-2-yloxymethyl) chroman 6-methoxymethoxy-2,5,7,8-tetramethyl-2- (5-nitropyridin-2-yloxymethyl)
Dissolve 5.2 g of chroman in 45 ml of acetic acid and add 10% to it.
Add 1 g of aqueous sulfuric acid and heat at 55-58 ° C for 15 minutes. After cooling, the reaction mixture is poured into 75 g of sodium hydrogen carbonate and 75 g of ice and extracted with ethyl acetate. The extract was washed with water and then dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product as a light brown oil.

Rf value of silica gel thin layer chromatography = 0.46
(Developing solvent; benzene: ethyl acetate = 10: 1) NMR spectrum (δppm, CDCl ₃ ): 1.39 (3H, s),
1.7-2.3 (2H, m), 2.05 (3H, s), 2.11 (3H, s), 2.15 (3H, s), 2.6
7 (2H, br.t, J = 6Hz), 4.19 (1H, s, disappears by adding heavy water), 4.
50 (2H, s), 6.85 (1H, d, J = 9Hz), 8,36 (1H, dd, J = 9 and 3H
z), 9.06 (1H, d, J = 3Hz).

Reference Example 32 (A-3-acylated) 6-acetoxy-2,5,7,8-tetramethyl-2-
(5-Nitropyridin-2-yloxymethyl) chroman According to Reference Example 7, 6-hydroxy-2,5,7,8-
The target product prepared from 5.2 g of tetramethyl-2- (5-nitropyridin-2-yloxymethyl) chroman, 3 ml of acetic anhydride, 3 ml of pyridine and about 20 ml of benzene has the following physical properties.

Rf value of silica gel thin layer chromatography = 0.52
(Developing solvent; benzene: ethyl acetate = 10: 1) NMR spectrum (δppm, CDCl ₃ ): 1.40 (3H, s),
1.7-2.3 (2H, m), 2.02 (9H, s), 2.32 (3H, s), 2.69 (2H, br.t, J
= 6Hz), 4.52 (2H, AB type, J = 12Hz), 6.86 (1H, d, J = 9Hz), 8.3
6 (1H, dd, J = 9 and 3Hz), 9.07 (1H, d, J = 3Hz).

Reference Example _{33 (A-3-H 2} ) 6- acetoxy-2- (5-Amino-2-yloxymethyl) 2,5,7,8-tetramethyl-chroman 6-acetoxy -2,5,7 , 8-Tetramethyl-2-
6 g of (5-nitropyridin-2-yloxymethyl) chroman was dissolved in a mixture of 80 ml of methanol and 15 ml of benzene in the presence of 1.5 g of 10% palladium on carbon.
The hydrogen pressure was reduced to about 1 atm for about 20 hours at room temperature. The palladium carbon was filtered off, and the obtained filtrate was concentrated under reduced pressure to obtain the desired product.

Rf value of silica gel thin layer chromatography = 0.04
(Developing solvent; benzene: ethyl acetate = 10: 1) NMR spectrum (δppm, CDCl ₃ ): 1.39 (3H, s),
1.6-2.4 (2H, m), 1.97 (3H, s), 2.01 (3H, s), 2.07 (3H, s), 2.3
0 (3H, s), 2.64 (2H, br.t, J = 6Hz), 3.9 (2H, br, s, disappears by adding heavy water), 4.25 (2H, AB type, J = 12Hz), 6.61 (1H , d, J ＝ 9H
z), 7.02 (1H, dd, J = 9 and 3Hz), 7.64 (1H, d, J = 3Hz).

Reference Example 34 (A-4) Ethyl 3- [2- (6-acetoxy-2,5,7,8)
-Tetramethylchroman-2-ylmethoxy) pyridin-5-yl] -2-chloropropionate According to Reference Example 9, 6-acetoxy-2- (5-aminopyridin-2-yloxymethyl) -2, 5,7,8-
4.5 g of tetramethylchroman, sodium nitrite 1.
The target product produced from 1 g, concentrated hydrochloric acid 5 ml, ethyl acrylate 10 g, cuprous oxide 175 mg, acetone 40 ml and water about 2.5 g has the following physical properties.

Rf value of silica gel thin layer chromatography = 0.45
(Developing solvent; benzene: ethyl acetate = 10: 1) NMR spectrum (δ ppm, CDCl ₃ ): 1.26 (3H, t, J
= 7.5Hz), 1.40 (3H, s), 1.7-2.3 (2H, m), 1.99 (3H, s), 2.02
(3H, s), 2.07 (3H, s), 2.31 (3H, s), 2.65 (2H, br.t, J = 6Hz),
3.07 (1H, dd, J = 13.5 and 7.5Hz), 3.30 (1H, dd, J = 13.5
And 7.5Hz), 4.0-4.5 (5H, m), 6.72 (1H, d, J = 9Hz), 7.48
(1H, dd, J = 9 and 3Hz), 8.02 (1H, d, J = 3Hz). Reference Example 35 (A-4) Ethyl 3- [4- (6-acetoxy-2,5,7,8)
-Tetramethylchroma 2-2-ylmethoxy) phenyl] -2-chloro-2-methylpropionate According to Reference Example 9, 6-acetoxy-2- (4-aminophenoxymethyl) -2,5,7, The target substance produced from 2 g of 8-tetramethylchroman, 25 ml of acetone, 3 ml of 35% hydrochloric acid, 0.7 g of sodium nitrite, 1 ml of water, 8 g of ethyl methacrylate, and 0.2 g of cuprous oxide had the following physical properties. Have.

Rf value of silica gel thin layer chromatography = 0.54
(Developing solvent; hexane: ethyl acetate = 2: 1) NMR spectrum (δppm, CDCl ₃ ): 1.29 (3H, t, J
= 7Hz), 1.43 (3H, s), 1.68 (3H, s), 1.98 (3H, s), 2.03 (3H,
s), 2.09 (3H, s), 2.32 (3H, s), 1.5-2.5 (2H, nd), 2.62 (2H, b
rt, J = 7Hz), 3.18 and 3.36 (2H, AB type, J = 17Hz), 3.84 and 3.98 (2H, AB type, J = 9Hz), 4.21 (2H, q, J = 7Hz), 6.84 (2
H, d, J = 9Hz), 7.14 (2H, d, J = 9Hz).

Reference Example 36 (H-1) 6-acetoxy-2-hydroxy-5,7,8-trimethyl-2- (4-nitrophenoxymethyl) -4-oxochroman 3-acetoxy-2,4,5-trimethyl-6 -(4-
To a solution of 15 g of nitrophenoxyacetoxy) acetophenone in 1 liter of tetrahydrofuran was added dropwise a solution of 3 g of potassium t-butoxide in 100 ml of tetrahydrofuran under ice cooling, and the mixture was stirred at the same temperature for 2.5 hours. The reaction mixture was poured into ethyl acetate and brine, the organic layer was separated, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 1: 1) to obtain the target compound.

Mp: 204-207 ° C. NMR spectrum _{(δppm, DMSO-d 6)} : 2.05 (3
H, s), 2.11 (3H, s), 2.34 (6H, s), 2.76 (1H, d, J = 17Hz), 3.24
(1H, d, J = 17Hz), 4.28 and 4.50 (2H, AB type, J = 10Hz), 7.2
4 (2H, d, J = 9Hz), 7.30 (1H, s, disappeared by adding heavy water), 8.24
(2H, d, J = 9Hz).

Reference Example 37 (H-2) 6-acetoxy-2- (4-aminophenoxymethyl)
2-Hydroxy-5,7,8-trimethyl-4-oxochroman According to Reference Example 11, 6-acetoxy-2-hydroxy-5,7,8-trimethyl-2- (4-nitrophenoxymethyl) -4. The target compound prepared from 7 g of oxochroman, 5 g of 10% palladium on carbon, 100 ml of tetrahydrofuran, and 100 ml of ethanol has the following physical properties.

Rf value of silica gel thin layer chromatography = 0.48
(Developing solvent; ethyl acetate) NMR spectrum (δppm, CDCl ₃ ): 2.08 (3H, s),
2.10 (3H, s), 2.32 (3H, s), 2.41 (3H, s), 2.78 and 3.03 (2
H, AB type, J = 16Hz), 3.4-4.3 (3H, br.s, lost by addition of heavy water), 3.98 and 4.12 (2H, AB type, J = 10Hz), 6.62 (2H, d, J = 9)
Hz), 6.80 (2H, d, J = 9Hz).

Reference Example 38 (H-3) Ethyl 3- [4- [6-acetoxy-2-hydroxy-5,7,8-trimethyl-4-oxochroman-2-
Ilmethoxy] phenyl] -2-chloropropionate According to Reference Example 9, 6-acetoxy-2- (4-aminophenoxymethyl) -2-hydroxy-5,7,8-trimethyl-4-oxochroman (3.4 g) , Acetone 40
ml, 35% hydrochloric acid 5 ml, sodium nitrite 1.2 g, water 1.6
ml, ethyl acrylate 13 g and cuprous oxide 0.32
The target compound produced from g has the following physical properties.

Rf value of silica gel thin layer chromatography = 0.20
(Developing solvent; hexane: ethyl acetate = 2: 1) NMR spectrum (δppm, CDCl ₃ ): 1.24 (3H, t, J
= 7Hz), 2.09 (6H, s), 2.33 (3H, s), 2.42 (3H, s), 2.5-3.6 (4
H, nd), 3.9-4.6 (5H, nd), 6.93 (2H, d, J = 9Hz), 7.20 (2H, d, J
= 9Hz).

Reference Example 39 6-t-Butoxycarbonylmethoxy-2,5,7,8
-Tetramethyl-2- (4-nitrophenoxymethyl)
-4-oxochroman 6-acetoxy-2,5,7,8-tetramethyl-2-
A mixture of 25 g of (4-nitrophenoxymethyl) -4-oxochroman, 30 ml of dimethylformamide and 150 ml of ethyl alcohol was ice-cooled, and a mixed solution of 5.6 g of sodium hydroxide, 150 ml of ethyl alcohol and 20 ml of water was added dropwise. Then, after stirring for 3 hours, 18.3 g of t-butyl bromoacetate was added dropwise, and the mixture was stirred at room temperature for 1 hour and left to stand overnight. The reaction mixture was poured into water, neutralized with 10% hydrochloric acid and then extracted with benzene.
The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 20: 1) to obtain the target compound.

Rf value (hereinafter, shown by silica gel thin layer chromatography): 0.49 (developing solvent; benzene: ethyl acetate = 10: 1) NMR spectrum (δ ppm, CDCl ₃ ): 1.53 (12H,
s), 2.07 (3H, s), 2.27 (3H, s), 2.57 (3H, s), 2.68 (1H, d, J = 1
6.5Hz), 3.05 (1H, d, J = 16.5Hz), 4.17 (2H, s, + 2H, AB type, J =
10Hz), 6.97 (2H, d, J = 9Hz), 8.19 (2H, d, J = 9Hz).

Reference Example 40 6-Ethoxy-2,5,7,8-tetramethyl-2-
(4-Nitrophenoxymethyl) chroman 6-hydroxy-2,5,7,8-tetramethyl-2-
(4-nitrophenoxymethyl) chroman 11 g and DM
55% oily sodium hydride in a mixture of 100 ml of F.
6 g was added and the mixture was stirred at room temperature for 1 hour. A mixture of 5.7 g of ethyl iodide and 5 ml of benzene was added dropwise under ice cooling, and the mixture was allowed to stand at room temperature for 2
Stir the time. The reaction mixture was poured into ice water and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; cyclohexane: benzene = 3: 7) to obtain the target compound.

Rf value: 0.48 (developing solvent; benzene) NMR spectrum (δ ppm, CDCl ₃ ): 1.39 (3H, t, J
= 7Hz), 1.43 (3H, s), 1.7-2.1 (2H, nd), 2.06 (3H, s), 2.14 (3
H, s), 2.17 (3H, s), 2.63 (2H, br.t, J = 7Hz), 3.72 (2H, q, J =
7Hz), 4.00 and 4.08 (2H, AB type, J = 10Hz), 6.98 (2H, d, J =
9Hz), 8.17 (2H, d, J = 9Hz).

Reference Example 41 2- (4-aminophenoxymethyl) -6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman 6-t-butoxycarbonylmethoxy-2,5,7,8
-Tetramethyl-2- (4-nitrophenoxymethyl)
A mixture of 17 g of 4-oxochroman, 3.5 g of 10% palladium on carbon, 150 ml of methanol, and 50 ml of dimethylformamide was added using a Parr hydrogenator.
The mixture was shaken at a hydrogen pressure of 3 to 5 atm for 7 hours. The palladium carbon was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in benzene, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the target compound.

Rf value: 0.29 (developing solvent; benzene: ethyl acetate =
4: 1) NMR spectrum (δppm, CDCl ₃ ): 1.47 (3H, s),
1.54 (9H, s), 2.11 (3H, s), 2.26 (3H, s), 2.55-2.75 (1H, nd),
2.57 (3H, s), 3.05 (1H, d, J = 16Hz), 3.15-3.65 (2H, br.s),
3.90 and 4.03 (2H, AB type, J = 10Hz), 4.17 (2H, s), 6.60 (2
H, d, J = 9Hz), 6.76 (2H, d, J = 9Hz).

Reference Example 42 2- (4-aminophenoxymethyl) -6-ethoxy-
2,5,7,8-Tetramethylchroman According to Reference Example 41, 6-ethoxy-2,5,7,8-tetramethyl-2- (4-nitrophenoxymethyl) chroman 11 g, 10% palladium carbon 2. The target compound was obtained from 2 g, 100 ml of methanol, and 30 ml of benzene.

Melting point: 121-123 ° C NMR spectrum (δppm, CDCl ₃ ): 1.38 (3H, t, J
= 7Hz), 1.40 (3H, s), 1.7-2.1 (2H, nd), 2.08 (3H, s), 2.12 (3
H, s), 2.17 (3H, s), 2.60 (1H, br.t, J = 7Hz), 3.1-3.6 (2H, b
r., disappeared by adding heavy water), 3.71 (2H, q, J = 7Hz), 3.80 and 3.9
1 (2H, AB type, J = 10Hz), 6.60 (2H, d, J = 9Hz), 6.78 (2H, d, J =
9Hz).

Reference Example 43 3- [4- (6-t-butoxycarbonylmethoxy-
2,5,7,8-tetramethyl-4-oxochroman-
2-ylmethoxy) phenyl] -2-chloropropionate ethyl 2- (4-aminophenoxymethyl) -6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman 16 g and acetone 160 ml 16 ml of concentrated hydrochloric acid, a solution of 3.1 g of sodium nitrite in water (7 ml), and 37 ml of ethyl acrylate were successively added dropwise to the mixture at 5 to 10 ° C. in a nitrogen stream. The internal temperature was adjusted to 40 to 43 ° C, and 0.5 g of cuprous oxide was gradually added. Generation of nitrogen is completed in about 30 minutes. The reaction mixture was poured into water and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (eluent; cyclohexane: ethyl acetate =
9: 1) to obtain the target compound.

Rf value: 0.33 (developing solvent; cyclohexane: ethyl acetate = 4: 1) NMR spectrum (δ ppm, CDCl ₃ ): 1.23 (3H, t, J
= 7.5Hz), 1.50 (3H, s), 1.53 (9H, s), 2.09 (3H, s), 2.26 (3H,
s), 2.5-2.8 (1H, nd), 2.57 (3H, s), 3.05 (1H, d, J = 16Hz), 3.
07 (1H, nd), 3.32 (1H, dd, J = 7 and 14Hz), 3.98 and 4.0
9 (2H, AB type, J = 10Hz), 4.05-4.35 (2H, nd), 4.18 (2H, s), 4.3
7 (1H, t, J = 7Hz), 6.85 (2H, d, J = 8Hz), 7.14 (2H, d, J = 8H
z).

Reference Example 44 2-chloro-3- [4- (6-ethoxy-2,5,7,
Ethyl 8-tetramethylchroman-2-ylmethoxy) phenyl] propionate According to Reference Example 43, 2- (4-aminophenoxymethyl) -6-ethoxy-2,5,7,8-tetramethylchroman 9.5 g, Concentrated hydrochloric acid 10 ml, sodium nitrite 2.
4 g, ethyl acrylate 26.8 g, cuprous oxide 0.4
g and 100 ml of acetone gave the desired compound.

Rf value: 0.30 (developing solvent; cyclohexane: ethyl acetate = 20: 1) NMR spectrum (δ ppm, CDCl ₃ ): 1.23 (3H, t, J
= 7Hz), 1.38 (3H, t, J = 7Hz), 1.41 (3H, s), 1.7-2.1 (2H, n
d), 2.07 (3H, s), 2.13 (3H, s), 2.17 (3H, s), 2.60 (2H, br.t, J
= 7Hz), 3.07 (1H, dd, J = 4 and 14Hz), 3.31 (1H, dd, J = 4
And 14Hz), 3.71 (2H, q, J = 7Hz), 3.86 and 3.96 (2H, AB
Type, J = 9Hz), 4.17 (2H, q, J = 7Hz), 4.36 (1H, t, J = 7.5Hz),
6.85 (2H, d, J = 9Hz), 7.13 (2H, d, J = 9Hz).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 31/425 AED C07D 311/22 7252-4C 311/58 7252-4C (72) Inventor Takeshi Fujita Sankyo stock company 1-25-2 Hiromachi, Shinagawa-ku, Tokyo (72) Inventor Tsutomu Kanai 1-25-2 Hiromachi Shinagawa-ku, Sankyo stock company (72) Inventor Mitsuro Yamazaki Tokyo 1-58, Hiromachi, Shinagawa-ku Sankyo Co., Ltd. (72) Inventor Kazuo Hasegawa Tokyo 1-2-58, Hiromachi, Shinagawa-ku Sankyo Co., Ltd. (72) Inventor Hokoshi Ohno Tokyo 1-2-58, Hiromachi, Shinagawa-ku Sankyo Co., Ltd. (56) References JP-A-60-51189 (JP, A)

Claims (1)

[Claims] 1. A general formula [In the formula (I), R ¹ represents a hydrogen atom, an alkyl group, an aralkyl group which may have a substituent or a cycloalkyl group which may have a substituent, and R ² represents a hydrogen atom or an alkyl group. represents a group, R ³ and described below R ^{3 'are} the same or different and represent a hydrogen atom or a hydroxyl protecting group,
R ⁴ represents a hydrogen atom, an alkyl group, an aralkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent or an alkoxy group. , R ⁵ represents a hydrogen atom, an alkyl group or an alkoxy group, R ⁶ and R ⁷ are the same or different and represent a hydrogen atom or an alkyl group, and R ⁸ is a hydrogen atom or an alkyl group which may have a substituent. Indicates R
⁹ represents a hydrogen atom, Ar represents a divalent aromatic ring group which may have a substituent or a pyridyl group, W represents a methylene group, a carbonyl group, a formula> CH—OR ³ ′ group (in the formula,
R ³ ′ has the same meaning as described above. ), The formula> = N-
OV group (in the formula, V represents a hydrogen atom, an alkyl group which may have a substituent or an aralkyl group which may have a substituent) or a formula> = N-OR ³ ′ _a group ( In the formula,
R ³ ′ _a represents a protective group for the hydroxyl group in R ³ ′ described above. Or a double bond may be formed with U described below, U is a single bond or a methylene group, or a double bond is formed with W, W is a carbonyl group, a formula> = N- When it represents an OV group or a formula> = N-OR ³ ′ _a group (in the formula, V and R ³ ′ _a have the same meanings as described above), a double bond may be formed together with R ¹ . n represents an integer of 1 to 10, Y represents an oxygen atom or an imino group, Z represents an oxygen atom or an imino group, or when W is a methylene group, it may represent a sulfur atom. ) A thiazolidine derivative or a salt thereof. However, in the formula (I), R ¹ and R ² are the same or different and represent a hydrogen atom or a lower alkyl group, and R ³ and R ³ ′ described later are the same or different and are a hydrogen atom, an aliphatic lower acyl group, an aliphatic group. A cyclic acyl group, an aromatic acyl group which may have a substituent, a heterocyclic acyl group, an aromatic aliphatic acyl group which may have a substituent, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group, Show, R
⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R ⁶ , R ⁷ , R
⁸ and R ⁹ represent a hydrogen atom, Ar represents a p-phenylene group, W represents a methylene group, a carbonyl group or a formula = C.
H-OR ³ ′ (R ³ ′ has the same meaning as described above), U represents a methylene group, and n
Represents an integer of 1 to 3, Y represents an oxygen atom or an imino group, Z represents an oxygen atom when W represents a methylene group,
A sulfur atom or an imino group, Z is or oxygen atom in the case of the proximal W is represented by a carbonyl group, or a group of the formula ^{= CH-OR 3 '(R} 3' have the same meanings as defined above.) A thiazolidine derivative represented by; or a salt thereof is excluded.