JPH072852A - Thiazoline derivative - Google Patents

Abstract

PURPOSE:To obtain a new thiazolidine derivative which is useful as a medicine for circulatory organs because it has actions to improve metabolism of lipid and glucose in blood and inhibit the aldose reductase. CONSTITUTION:A compound of the formula [R<1> is H, alkyl, aralkyl which may be substituted, cycloalkyl which may be substituted; R<2> is H, alkyl; R<3> is H, OH-protecting group; R<4> is R<1>, aryl, alkoxy both of which may be substituted; R<5> is H, alkyl, alkoxy; R<6>, R<7> are H, alkyl; R<8> is H, alkyl which may be substituted; R<9> is alkyl which may be substituted; Ar is divalent aromatic or aromatic heterocyclic groups which may be substituted; W is CH2, CO, CH, OR<3>' (R<3>' is R3), N-OV (V is H, alkyl, aralkyl both of which may be substituted); U is a single bond, CH2 or to form a double bond together with W; n is 1 to 10; Y, Z are O, NH, or X in case that W is CH2), for example, 5-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4- dioxothiazolidine-3-acetic acid t-butyl ester.

Description

Detailed Description of the Invention

[0001]

[Object of the Invention]

[0002]

TECHNICAL FIELD The present invention relates to a thiazolidine derivative having an action of improving lipid metabolism in blood, an action of improving blood glucose metabolism, and an aldose reductase inhibitory action.

[0003]

2. Description of the Related Art Conventionally, thiazolidine derivatives have the effects of lowering blood lipids and blood glucose, as disclosed in JP-A-55-22636 and Chem. Pharm. Bull. 30 , 3580 (198).
Known in 2).

[0004]

DISCLOSURE OF THE INVENTION The present inventors have conducted diligent research 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, The present invention has been completed by finding that it has a blood glucose metabolism improving action and an aldose reductase inhibitory action and has extremely low toxicity.

[0005]

[Constitution of the invention]

[0006]

The novel thiazolidine derivative of the present invention has the general formula

[0007]

[Chemical 2]

It includes a compound represented by or a salt thereof.

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 group, R ³ and R ³ ′ described later are the same or different and represent a hydrogen atom or a hydroxyl-protecting group, and R ⁴ may have a hydrogen atom, an alkyl group or a substituent. An aralkyl group, a cycloalkyl group which may have a substituent, an aryl group or an alkoxy group which may have a substituent, R ⁵ represents a hydrogen atom, an alkyl group or an alkoxy group, R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or an alkyl group,
R ⁸ represents a hydrogen atom or an alkyl group which may have a substituent, R ⁹ represents a hydrogen atom or an alkyl group which may have a substituent, and Ar represents a substituent. shows good bivalent aromatic ring group or substituted or divalent be heteroaromatic ring group, W is a methylene group, a carbonyl group, the formula> CH-oR ³ 'group (wherein, R ^3' Has the same meaning as described above.), A formula> = N-OV group (in the formula, V is a hydrogen atom, an alkyl group which may have a substituent or an aralkyl which may have a substituent). A group) or a formula> = N-OR ³ ′ _a group (wherein R ³ ′ _a represents _a hydroxyl-protecting group for R ³ ′ described above) or a double bond together with U described later. And U represents a single bond or a methylene group, or forms a double bond with W, There carbonyl group, the formula> = N-OV
Group or the formula> = N-OR ³ 'in _a group (wherein, V, R ^3'
_a has the same meaning as described above. ) Indicates R
^A double bond may be formed together with ¹ , n is an integer of 1 to 10, Y is an oxygen atom or an imino group, Z is an oxygen atom or an imino group, or W is a methylene group. May also represent a sulfur atom.

In the above general formula (I), R ¹ is a hydrogen atom, a linear or branched alkyl group having 1 to 25 carbon atoms, or an aralkyl having 7 to 10 carbon atoms which may have a substituent. Group or 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, R 2 ³ has a hydrogen atom, a carboxy group as a substituent, 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. A linear or branched alkyl group having 1 to 10 carbon atoms, which may have an unsaturated bond, or a carbon which may have a substituent. Aliphatic acyl group having 1 to 23,
Alicyclic acyl group, optionally substituted aromatic acyl group, heterocyclic acyl group, optionally substituted aromatic aliphatic acyl group, alkoxycarbonyl group, aralkyloxycarbonyl group or alkyl Group, a carbamoyl group which may be substituted with an aralkyl group or an aryl group, R ³ ′ represents a hydrogen atom or the acyl group in the above R ³ , and R ⁴ represents a hydrogen atom, a straight chain or a branched chain. An alkyl group having 1 to 20 carbon atoms, an aralkyl group having 7 to 10 carbon atoms which may have a substituent, a cycloalkyl group having 5 to 8 carbon atoms which may have a substituent, and a substituent Optionally represents an aryl group or a linear or branched alkoxy group having 1 to 12 carbon atoms, R ⁵
Is a hydrogen atom, a straight or branched chain carbon atom having 1 to 2
0 represents an alkyl group or a linear or branched alkoxy group having 1 to 12 carbon atoms, and R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or a linear or branched carbon number. 1 shows a 4 alkyl groups, R ⁸ represents a hydrogen atom or an alkyl group of the aforementioned R ³ and substituted carbon atoms and optionally 1 to 10 having the same meanings, R ⁹
Represents an optionally substituted alkyl group having 1 to 10 carbon atoms having the same meaning as R ³ described above, and Ar represents a divalent aromatic ring group which may have a substituent, or a substituent. indicates also be divalent heteroaromatic ring group, W is a methylene group, a carbonyl group, the formula> = CH-OR ³ 'group (wherein, R ^3' have the same meanings as defined above.), formula > = N-OV group (in the formula, V is a hydrogen atom, which may have a substituent having the same meaning as that of R ³ described above, which may have a linear or branched chain and has 1 to 10 carbon atoms. an alkyl group or substituent having optionally aralkyl group which may a carbon number of 7 to 11.) ^{or> = N-O-R 3} 'a ( wherein, R ^3' _a
Represents a group having the same meaning except for the hydrogen atom 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, and formula> = N -OV group or formula> = N
When it represents _a —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, and Z represents an oxygen atom or an imino group. Or may represent a sulfur atom when W is a methylene group.

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 , Eicosile,
3,7,11,15-tetramethyl-hexadecyl, it may be mentioned a straight or branched chain carbon atoms 1 to 25, such as docosyl or pentacosyl; R ¹ is,
When an aralkyl group which may be substituted is shown, examples of R ¹ include those having 7 to 10 carbon atoms such as benzyl, phenethyl, 3-phenylpropyl, and 4-phenylbutyl. Methyl,
Examples include lower alkyl groups such as ethyl and propyl, lower alkoxy groups such as methoxy, ethoxy and propoxy, and halogen atoms such as fluorine, chlorine, bromine and iodine; R ¹ represents a cycloalkyl group which may be substituted. In this case, 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,
The same or different as R ³ , R ⁸ , R ⁹ and V, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl,
A linear or branched alkyl group having 1 to 10 carbon atoms such as 2-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, neohexyl, heptyl, octyl, nonyl or decyl or the formula R ^10- (Alk) −
A group (in the formula, Alk is methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene,
Decamethylene,

[0014]

[Chemical 3]

A linear or branched alkylene group having 1 to 10 carbon atoms, such as a group, wherein R ¹⁰ is a carboxy group, methoxycarbonyl, ethoxycarbonyl or ter.
an alkoxycarbonyl group having 2 to 5 carbon atoms which may be substituted with a hydroxyl group or a lower alkoxy group such as t-butoxycarbonyl, hydroxyethoxycarbonyl or methoxyethoxycarbonyl, a carbamoyl group, N-methylcarbamoyl, N-ethylcarbamoyl, Mono- or dialkyl-substituted carbamoyl groups such as N, N-dimethylcarbamoyl or N, N-diethylcarbamoyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl or 4-methyl-1-piperazinyl, 4-phenyl- 5- or 6-membered cyclic aminocarbonyl group which may have a substituent such as 1-piperazinyl and 4-acetyl-1-piperazinyl, hydroxyl group, methoxy, ethoxy, propoxy, isopropoxy, butoxy A straight-chain or branched C1-C5 alkoxy group such as isobutoxy or pentyloxy, and a C2-C5 aliphatic such as acetoxy, propionyloxy, butyryloxy, isobutyryloxy or pivaloyloxy. Acyloxy group, or benzoyloxy, p-toluoyloxy, o-anisoyloxy, 3-fluorobenzoyloxy, 4-
It represents an aromatic acyloxy group such as chlorobenzoyloxy, 4-aminobenzoyloxy or 4-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, octa. Decanoyl, Nonadecanoyl, 2, 6, 1
0,14-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-carboxypropenoyl, trans
An aliphatic acyl group having 1 to 23 carbon atoms which may have an unsaturated bond such as -3-carboxypropenoyl (wherein the acyl group is a carboxy group, a lower alkoxycarbonyl group or an optionally substituted aryloxy group); A carbonyl group may be substituted), cyclopentanecarbonyl,
Alicyclic acyl groups such as cyclohexanecarbonyl, cycloheptanecarbonyl, benzoyl, p-toluoyl, 4-nitrobenzoyl, 3-fluorobenzoyl,
2-chlorobenzoyl, 4-aminobenzoyl, 3-dimethylaminobenzoyl, 2-methoxybenzoyl,
Aromatic acyl groups such as 3,4-dichlorobenzoyl, 3,5-di-t-butyl-4-hydroxybenzoyl, 1-naphthoyl, 2-furoyl, 3-thenoyl, 3-pyridinecarbonyl, 4-pyridinecarbonyl A heterocyclic acyl group such as, phenylacetyl, 4-chlorophenylacetyl, 3-phenylpropionyl, an aromatic aliphatic acyl group which may have a substituent such as cinnamoyl and may have an unsaturated bond, Lower alkoxy or aralkyloxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl or carbamoyl, N, N-dimethylcarbamoyl,
N, N-diphenylcarbamoyl, N-benzyl-N-
A substituted or unsubstituted carbamoyl group such as propylcarbamoyl and the like can be mentioned.

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-nitrobenzoyl. Examples of such aromatic acyl groups include R ³ ′ and sulfonyl groups such as methanesulfonyl, benzenesulfonyl and 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
-Straight or branched carbon number 1 to 1 such as ethylhexyl, 1,1,3,3-tetramethylbutyl, nonyl, decyl, 3,7-dimethyloctyl, undecyl, dodecyl, pentadecyl or eicosyl. There are 20 things.

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 or 1-methyl. Examples include -1- (4-methylphenyl) ethyl, 2-phenylethyl, 2- (3-methoxyphenyl) -1,1-dimethylethyl, 3- (2-chlorophenyl) propyl, 4-phenylbutyl and the like. .

R ⁴ has 5 carbon atoms which may have a substituent.
8 represents a cycloalkyl group, R ⁴ is cyclopentyl, cyclohexyl, 1-methylcyclohexyl, 2-methylcyclohexyl, 1-ethylcyclohexyl, 1-propylcyclohexyl, 1-isobutylcyclohexyl, cycloheptyl, 1-methylcycloheptyl. , Or cyclooctyl.

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

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

When R ⁵ represents an alkyl group, R ⁵ is a straight chain such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, heptyl, octyl, decyl, dodecyl, pentadecyl, eicosyl and the like. -Like or branched carbon number 1
To 20.

When R ⁵ represents an alkoxy group, R ⁵ is methoxy, ethoxy, propoxy, isopropoxy,
Examples include butoxy, octyloxy, dodecyloxy and the like. In addition, adjacent R ⁴ and R ⁵ may represent a lower alkylenedioxy group such as methylenedioxy or ethylenedioxy which are formed together; further, R ⁴ and R ⁵ are taken together and are substituted. Represents a group which may have a group —CH═CH—CH═CH—, and may form a naphthalene ring with an adjacent benzene ring,
Examples of the substituent include a lower alkyl group such as methyl, ethyl and isopropyl, and a lower alkoxy group such as methoxy and ethoxy.

When R ⁶ and R ⁷ represent an alkyl group,
R ⁶ and R ⁷ may be 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 an m-phenylene group, in which case the substituent R of Ar is R. ¹¹ is a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, or pentyl,
Methoxy, ethoxy, isopropoxy, t-butoxy,
Or it may be a lower alkoxy group such as 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:

[0028]

[Chemical 4]

(In the above formula, Q represents an oxygen atom, a sulfur atom, or an imino group), in which case A
Examples of the substituent R ¹¹ of r include a lower alkyl group such as methyl, ethyl, isopropyl, t-butyl, or pentyl, and a lower alkoxy group such as methoxy, ethoxy, isopropoxy, t-butoxy, or pentyloxy. To be

W is a methylene group; a carbonyl group;
Formula> CH—OR ³ ′ group (wherein R ³ ′ has the same meaning as described above); Formula ≧ = NOV group [wherein V is a hydrogen atom and has the same meaning as R ³ described above] A linear or branched alkyl group having 1 to 10 carbon atoms which may have a substituent or benzyl, 4-methylbenzyl, 3-methoxybenzyl, 1-chlorobenzyl, 1-phenylethyl, 2 An aralkyl group having 7 to 11 carbon atoms which may have a substituent, such as -phenylethyl, 3- (2-chlorophenyl) propyl or 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl. Or _a group> = N-OR ³ ′ _a group (in the formula, R ³ ′ _a has the same meaning as described above).
A double bond may be formed together therewith.

U usually represents a methylene group, but may also represent a double bond together with W. U further, W is a carbonyl group, the formula> = N-OV group (wherein, V is the same meanings as those described above.) Or the formula> = N-OR ³ _'a group (wherein,
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, and W
When is a methylene group, it can also represent a sulfur atom.

The desired compound represented by the above general formula (I) of the present invention can be converted into a pharmaceutically acceptable non-toxic salt according to a conventional method. Examples of such salts include alkali salts such as sodium and potassium. Examples thereof include metal salts and salts of alkaline earth metals such as calcium.

When the object 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 or nitrate. , Inorganic salts such as phosphates; acetates, succinates, maleates, fumarates, malates,
Examples thereof include organic acid salts such as glutamate, aspartate, paratoluenesulfonate and methanesulfonate.

Further, in the object compound represented by the general formula (I) of the present invention, preferable compounds include R ¹
Is a hydrogen atom or a linear or branched alkyl group having 1 to 20 carbon atoms, and further a linear or branched alkyl group having 1 to 12 carbon atoms, and particularly linear or branched. A chain alkyl group having 1 to 9 carbon atoms; R
² is a hydrogen atom or a lower alkyl group, more preferably a hydrogen atom or a methyl or isopropyl group, especially a methyl group; R ³ is a hydrogen atom, and may be substituted, straight-chain or branched-chain C 1 To an alkyl group of 5 to 5 [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 linear or branched group). (May be substituted with a branched C1 to C5 alkoxy group), a hydroxyl group, a linear or branched C1 to C5 alkoxy group, or a C2 to C5 aliphatic And benzoyloxy which may be substituted with an acyloxy group, 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 carboxy group as a substituent, an alkoxycarbonyl group having 2 to 5 carbon atoms, 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 the formula

[0037]

[Chemical 5]

[0038] 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 preferred Is a hydrogen atom; R ⁴ is a linear or branched carbon atom having 1
To 12 alkyl groups, more preferably linear or branched alkyl groups having 1 to 9 carbon atoms, particularly methyl, isopropyl, t-butyl, t-pentyl, 1,1- Dimethylbutyl, 1,1-diethylpropyl or 1,1,3,3-tetramethylbutyl group; R ⁵ represents 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; preferred substituents for R ⁸ are hydrogen atoms or substituted alkyl groups having the same meaning as R ³ , especially hydrogen atoms; preferred substituents for R ⁹ are R ³
A substituted alkyl group having the same meaning as above, further an alkoxycarbonylalkyl group or a carboxyalkyl group, particularly a methoxycarbonylmethyl group or a carboxymethyl group; Ar is a p-phenylene group, an o-phenylene group, or a m-phenylene group. Group or expression

[0039]

[Chemical 6]

When p-
Phenylene group, m-phenylene group, or formula

[0041]

[Chemical 7]

Is a p-phenylene group; R ¹¹ is a lower alkyl group, especially a methyl group; W is a methylene group, a carbonyl group,

[0043]

[Chemical 8]

And in particular methylene, carbonyl or the formula> = N-OH, more especially methylene; U is a double bond together with methylene or R ¹ , especially methylene. Compounds in which n is 1, 2 or 3, more preferably 1 or 2, especially 1, Y is an oxygen atom; Z is an oxygen atom or an imino group, especially an oxygen atom.

Specific examples of the compound in which R ⁹ is a hydrogen atom, which is the starting compound for the thiazolidine derivative (I) of the present invention, include, for example, compounds having the structural formulas shown below (Tables 1 to 5). Can be given.

In the table below, Me- represents methyl substitution.

[0047]

[Chemical 9]

[0048]

[Table 1]

[0049]

[Table 2]

[0050]

[Table 3]

[0051]

[Table 4]

[0052]

[Table 5]

[0053]

[Table 6]

[0054]

[Table 7]

[0055]

[Table 8]

[0056]

[Table 9]

[0057]

[Table 10]

[0058]

[Table 11]

[0059]

[Table 12]

[0060]

[Table 13]

[0061]

[Table 14]

[0062]

[Table 15]

[0063]

[Table 16]

[0064]

[Table 17]

[0065]

[Table 18]

[0066]

[Table 19]

[0067]

[Table 20]

[0068]

[Table 21]

[0069]

[Table 22]

[0070]

[Table 23]

[0071]

[Table 24]

[0072]

[Table 25]

[0073]

[Table 26]

[0074]

[Table 27]

[0075]

[Table 28]

[0076]

[Table 29]

[0077]

[Table 30]

[0078]

[Table 31]

[0079]

[Table 32]

[0080]

[Table 33]

[0081]

[Table 34]

[0082]

[Table 35]

[0083]

[Table 36]

[0084]

[Table 37]

[0085]

[Table 38]

[0086]

[Table 39]

[0087]

[Table 40]

[0088]

[Table 41]

[0089]

[Table 42]

[0090]

[Table 43]

[0091]

[Table 44]

[0092]

[Table 45]

[0093]

[Table 46]

[0094]

[Table 47]

[0095]

[Table 48]

[0096]

[Table 49]

[0097]

[Table 50]

[0098]

[Table 51]

[0099]

[Table 52]

[0100]

[Table 53]

[0101]

[Table 54]

[0102]

[Table 55]

[0103]

[Table 56]

[0104]

[Table 57]

[0105]

[Table 58]

Further, there are compounds (Table 2) having the following structural formulas.

[0107]

[Chemical 10]

[0108]

[Table 59]

[0109]

[Table 60]

[0110]

[Table 61]

[0111]

[Table 62]

[0112]

[Table 63]

[0113]

[Table 64]

Further, compounds having the structural formulas shown below (Table 3) can be mentioned.

[0115]

[Chemical 11]

[0116]

[Table 65]

[0117]

[Table 66]

[0118]

[Table 67]

[0119]

[Table 68]

[0120]

[Table 69]

In the table below, 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 represents a 3,7-dimethyloctyl group, and 7,7-dMO represents a 7,7-dimethyloctyl group.

[0122]

[Table 70]

[0123]

[Table 71]

[0124]

[Table 72]

[0125]

[Table 73]

[0126]

[Table 74]

[0127]

[Table 75]

[0128]

[Table 76]

[0129]

[Table 77]

[0130]

[Table 78]

[0131]

[Table 79]

[0132]

[Table 80]

[0133]

[Table 81]

[0134]

[Table 82]

[0135]

[Table 83]

[0136]

[Table 84]

Next, specific examples of the compound having the general formula (I) of the present invention include compounds having the structural formulas shown below (Tables 6 to 12). However, the first
In Table 1 and Table 12, compounds in which R ⁹ represents a hydrogen atom are specific examples of the starting material compound of the present invention.

[0138]

[Table 85]

[0139]

[Table 86]

[0140]

[Table 87]

[0141]

[Table 88]

[0142]

[Table 89]

[0143]

[Table 90]

[0144]

[Table 91]

[0145]

[Table 92]

[0146]

[Table 93]

[0147]

[Table 94]

[0148]

[Table 95]

[0149]

[Table 96]

[0150]

[Table 97]

[0151]

[Table 98]

[0152]

[Table 99]

[0153]

[Table 100]

[0154]

[Table 101]

[0155]

[Table 102]

[0156]

[Table 103]

[0157]

[Table 104]

The thiazolidine derivative (I) of the present invention can be produced, for example, as follows. That is, it is obtained by alkylating a compound in which R ⁹ is a hydrogen atom in formula (I). In the formula (I), the compound (III) in which W is a methylene group or a carbonyl group and Z is an imino group is represented by the general formula (II)

[0159]

[Chemical 12]

It is obtained by reacting the compound represented by ## STR14 ## with 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, and A
Is a cyano group, a carboxy group, for example, an alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, a carbamoyl group or the formula -CO.
Represents an OM group (wherein M represents a metal atom such as sodium, potassium, calcium, aluminum or an equivalent cation such as ammonium), and X represents a halogen atom such as chlorine, bromine, or iodine. Represent. The compound (III) may be a tautomer as shown below, but for convenience, these are simply represented by the formula (III).

When Y is an oxygen atom

[0163]

[Chemical 13]

When Y is an imino group,

[0165]

[Chemical 14]

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 used is not particularly limited, but it is preferable to use a slight excess of thiourea relative to the compound (II) in an equimolar amount. It is preferably 1 to 2 mol 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, solvent and the like used, but the reaction is usually carried out at the boiling point of the solvent or at 80 to 150 ° C. for 1 hour to about 20 hours.

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

[0168]

[Chemical 15]

As shown below, the compound (IV)
Tautomers are possible, but for convenience, these are simply represented by the formula (I
V).

[0170]

[Chemical 16]

In the hydrolysis step, the compound (III) is treated with a suitable solvent (eg, sulfolane, methanol, ethanol, ethylene glycol monomethyl ether, etc.), water, an organic acid such as acetic acid, or a mineral acid such as sulfuric acid or hydrochloric acid. It is carried out by heating in the presence. The amount of the acid added is usually 0.1 to 10 mol, preferably 0.2 to 3 mol, relative to 1 mol of the compound (III), and the amount of water or an aqueous solvent added is usually in a large excess relative to the compound (III). Is. The reaction temperature is usually 50 to 100 ° C., and the heating time is usually several hours to about 20 hours. After the hydrolysis step, R ³ in the compound (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.

[0172]

[Chemical 17]

The thiazolidine derivative (IV) obtained in the step is exemplified by a conventional method with an alkali metal such as sodium or potassium; an alcal earth metal such as calcium; or a trivalent metal such as aluminum. Various metals; preferably alkali metals such as sodium and potassium; alkaline earth metals such as calcium; and more preferably, salts with alkali metals such as sodium and potassium can be formed.

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, inorganic acid salts such as hydrochloride, sulfate, nitrate and phosphate, if desired;
It can be led to organic acid salts such as acetate, succinate, maleate, fumarate, malate, glutamate, aspartate, paratoluenesulfonate, methanesulfonate.

(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, and a mineral acid such as hydrochloric acid or sulfuric acid, By using a dehydrating agent or dehydrating catalyst composed of an organic acid such as p-toluenesulfonic acid, the desired ester can be converted. The reaction is usually performed in a solvent. As the solvent to be used, ethers such as ether, tetrahydrofuran and dioxane, benzene, aromatic hydrocarbons such as toluene, hexane,
Aliphatic hydrocarbons such as cyclohexane and heptane,
Dichloromethane, halogenated hydrocarbons such as chloroform, acetone, ketones such as methyl ethyl ketone, amides such as dimethylformamide and dimethylacetamide, pyridine, organic bases such as triethylamine, sulfoxides such as dimethyl sulfoxide, Examples thereof include sulfones such as sulfolane and water. The ratio of the compound (IV _H ) 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 (IV _H ). Preferably the compound (I
The acylating agent is 1 to 10 mol per 1 mol of V _H ).
The reaction conditions such as reaction temperature and reaction time depend on the raw materials used,
Usually 0 ° C to 100 ° C, depending on the solvent
It takes 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 sodium borohydride,
It is obtained by reacting a reducing agent such as K-selectride, especially sodium borohydride.

[0178]

[Chemical 18]

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 (VI).

When Y is an oxygen atom

[0181]

[Chemical 19]

When Y is an imino group,

[0183]

[Chemical 20]

The reaction of compound (V) with 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 (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 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 100 ° C. for 1 hour to about 20 hours.

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

[0186]

[Chemical 21]

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 (VIII).

[0188]

[Chemical formula 22]

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, and ethers such as tetrahydrofuran and dioxane. The molar ratio of the compound (VII) and sodium borohydride used is not particularly limited, but it is preferable to use sodium borohydride in excess 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 reaction temperature and reaction time will differ depending on the starting materials, solvent and the like used, but the reaction is usually at 0 to 100 ° C. for 1 hour to about 20 hours.

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.

[0191]

[Chemical formula 23]

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 have tautomers as shown below, but for convenience, these are simply represented by the formula (IX).

When Y is an oxygen atom

[0194]

[Chemical formula 24]

When Y is an imino group

[0196]

[Chemical 25]

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 (VI) to the acylating agent is not particularly limited, but it is preferable to use the acylating agent in a slightly excess amount over the equimolar amount with respect to the compound (VI). The amount of the acylating agent is preferably 1 to 10 mol, based on 1 mol of the compound (VI).
The reaction conditions such as reaction temperature and reaction time depend on the raw materials used,
It depends on the type of solvent, but usually 0 to 100 °
It takes several minutes to about 20 hours.

The compound (VIII) can be converted to the desired acyl compound (X) by reacting with an acylating agent such as an acid halide or an acid anhydride.

[0200]

[Chemical formula 26]

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).

[0202]

[Chemical 27]

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 (VIII) to the acylating agent is not particularly limited, but it is preferable to use the acylating agent in a slightly equimolar amount 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 raw materials used and the type of solvent used, but they are usually 0 to 100 ° C. and several minutes to about 20.
It's time.

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

[0205]

[Chemical 28]

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

[0208]

[Chemical 29]

When Y is an imino group,

[0210]

[Chemical 30]

The reaction for eliminating water or R ³ ′ _a OH from compound (VI) or (IX), respectively, is carried out in the presence or absence of an acid catalyst, usually in a solvent. The reaction may be carried out in an acidic solvent without particularly using. 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 0.1 mol% to 100 mol% with respect to the compound (VI) or (IX), preferably 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 to 100 ° C. and several minutes to about 20 hours.

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

[0214]

[Chemical 31]

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).

[0216]

[Chemical 32]

The reaction for eliminating water or R ³ ′ _a OH from compound (VIII) or (X), respectively, is generally carried out in a solvent in the presence or absence of an acid catalyst. The reaction may be carried out in an acidic solvent without particularly using. 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, 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 catalyst is not particularly limited, but is 0.1 mol% to 100 mol% with respect to the compound (VIII) or (X).
And preferably 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, etc., but are usually 0 to 100 ° C., and are several minutes to about 20 hours.

In formula (I), a compound (XII) in which W and U form a carbon-carbon double bond and Z is an oxygen atom is obtained by hydrolyzing a compound (XI) in which Z is an imino group. Can also be manufactured.

[0220]

[Chemical 33]

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, the compound (XI) is treated with a suitable solvent (eg, sulfolane, methanol, ethanol, ethylene glycol monomethyl ether, etc.), water, an organic acid such as acetic acid, or a mineral acid such as sulfuric acid or hydrochloric acid. It is carried out by heating in the presence. The amount of the acid added is usually 0.1 to 10 mol, preferably 0.2 to 3 mol, relative to 1 mol of the compound (XI), and the amount of water or the aqueous solvent added is usually in a large excess relative to the compound (XI). Is. 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, R ³ in the compound (XII) 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.

[0223]

[Chemical 34]

In the formula (I), a compound in which W is a methylene group and Y and Z are both oxygen atoms [IV, (W ₁ = C
H ₂ )] can be produced by hydrogenating a compound (XII) in which W and U in the formula (I) form a carbon-carbon double bond, and Y and Z are both oxygen atoms. . 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.

[0225]

[Chemical 35]

A catalytic reduction method is used as the hydrogenation reaction. The catalyst used for catalytic reduction is palladium-carbon,
Raney-nickel, platinum oxide and the like can be mentioned, but palladium-carbon is preferable. Hydrogen pressure is 1 atm to 1
The pressure is 00 atm, but preferably 1 atm to 6 atm. As the solvent, 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 the reaction time will differ depending on the starting materials and solvent used, but are usually at room temperature to 50 ° C. for several minutes to about 20.
It's time.

In formula (I), W represents a carbonyl group, and U
Is a double bond together with R ¹ and both Y and Z are oxygen atoms, the compound (XV) is a compound represented by the general formula (XIII) or a compound represented by the general formula (XIV) obtained from thiourea. Manufactured via In formula (XIII), (XIV), or (XV),

[0228]

[Chemical 36]

R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R
⁸ ′, A, Ar, n, X, Y, and Z have the same meanings as described above, L is —OR ³ (R ³ has the same meaning as described above), or two together with U. It represents a heavy bond, and U represents a methylene group when L is —OR ³ (R ³ has the same meaning as described above). 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). , Respectively represented as formula (XIV) and formula (XV).

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

In the formula (I), W is the formula> = N-OV (in the formula,
V has the same meaning as described above. ) And Z is an imino group, a compound represented by the general formula H ₂ N—O can be obtained by converting a compound represented by the general formula (V ′) in which W is a carbonyl group.
It is obtained by reacting a compound having V (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).

[0232]

[Chemical 37]

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. The compound (XVI) may have tautomers, for example, as shown below, but for convenience, these are simply represented by the formula (XVI).

When Y is an oxygen atom,

[0235]

[Chemical 38]

When Y is an imino group,

[0237]

[Chemical Formula 39]

The reaction between the compound (V ′) and the compound: H ₂ NOV (the compound may be the above-mentioned salt, and V has the same meaning as described above) is usually sodium hydroxide, Compound 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: H ₂ NOV (the compound is the above-mentioned salt And V has the same meaning as described above.), And V is achieved by reacting hydroxylamine derivatives represented by the above formula.

The reaction between the compound (V ') and the compound having the formula H ₂ NOV is usually carried out in a solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol, butanol and ethylene glycol monomethyl ether, tetrahydrofuran,
Ethers such as dioxane, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, sulfones such as sulfolane, organic bases such as triethylamine and pyridine, or water, or these A mixed solvent may be used.

In the reaction of the compound (V ′) with the hydroxylamine derivative represented by the formula H ₂ NOV, the molar ratio used is not particularly limited, but the compound (V ′) has the formula H ₂ NOV. The compound may be in a large excess over an equimolar amount, preferably with respect to 1 mol of the compound (V '), the compound of the formula H
_The compound having ₂ NOV is 1 to 50 mol. Formula H
_{2 When the} compound having NOV is an inorganic acid salt of hydroxylamine derivatives, a deoxidizing agent may be used in the reaction, and the molar ratio of the deoxidizing agent to the inorganic acid salt is equal to that of the inorganic acid salt. It may be not more than 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 0 to 100 ° C. and several minutes to about 10 days.

Particularly, in the formula (I), a compound (XVII) in which W is the formula> = N-OV (wherein V has the same meaning as described above) and both Y and Z are oxygen atoms. Is a compound represented by the general formula (VII ′) in which W represents a carbonyl group, and may be a compound represented by 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 is as described above). Which has the same meaning as that of the above).

[0243]

[Chemical 40]

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 by the formula (XV
Represented as II).

[0245]

[Chemical 41]

The reaction between the compound (VII ') and the compound having the formula H ₂ NOV (wherein the compound may be the salt mentioned above, V has the same meaning as described above), the reaction is usually sodium hydroxide. , A compound having the formula H ₂ NOV 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. It may be the above-mentioned salt, and V has the same meaning as the above-mentioned.) It is achieved by reacting hydroxylamine derivatives represented by the above formula.

The reaction between the compound (VII ') and the compound having the formula H ₂ NOV is usually carried out in a solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol, butanol and ethylene glycol monomethyl ether, tetrahydrofuran,
Ethers such as dioxane, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, sulfones such as sulfolane, organic bases such as triethylamine and pyridine, or water, or these A mixed solvent may be used.

[0248] Compound (VII ') in a reaction with the hydroxylamine derivatives represented by compounds having the formula H ₂ NOV, its use molar ratio is not particularly limited, Compound (VII' formula H ₂ relative to) The compound having NOV 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 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.

[0249] formula (I), W has the ^{formula> = N-O-R 3} 'a
(Wherein R ³ ′ _a has the same meaning as described above), and the compound (XX) in which Z is an imino group is a compound in which V is a hydrogen atom in the above general formula (XVI). (XVIII)
To an acylating agent such as an acid halide or an acid anhydride.

[0250]

[Chemical 42]

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 meanings as described above. The compound (XX) may be a tautomer, for example, as shown below, but for convenience, these are simply represented as formula (XX).

When Y is an oxygen atom,

[0253]

[Chemical 43]

When Y is an imino group,

[0255]

[Chemical 44]

The reaction of compound (XVIII) with the acylating agent is usually carried out 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 (XVIII) and the acylating agent is
Although there is no particular limitation, it is preferable to use an excess of an acylating agent with respect to the compound (XVIII) in an equimolar amount, and preferably 1 to 10 mol of the acylating agent with respect to 1 mol of the compound (XVIII). 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 formula> = N-O-
R ³ ′ _a (wherein R ³ ′ _a has the same meaning as described above) and Y and Z are both oxygen atoms (XX
I) can be obtained by reacting the compound (XIX) in the above general formula (XVII), in which V is a hydrogen atom, with an acylating agent such as an acid halide or an acid anhydride.

[0258]

[Chemical formula 45]

In the above formulas (XIX) and (XXI), R ¹ ,
^{R 2, R 3, R 3} 'a, R 4, R 5, R 6, R 7,
R ⁸ ′, Ar, U and n have the same meanings as described above. The compound (XXI) may be a tautomer, for example, as shown below, but for convenience, these are simply represented by the formula (XXI).

[0260]

[Chemical formula 46]

The reaction between compound (XIX) and the acylating agent is
It is usually carried out in a solvent. As the solvent used,
Ethers such as ether, 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. , Pyridine, organic bases such as triethylamine, dimethylformamide,
Examples thereof include amides such as dimethylacetamide, sulfoxides such as dimethylsulfoxide, sulfones such as sulfolane and water, or a mixed solvent thereof. The ratio of the compound (XIX) to the acylating agent is not particularly limited, but it is preferable to use an acylating agent in an equimolar excess with respect to the compound (XIX), and preferably the compound (XIX)
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, the type of solvent used, etc., but are generally 0 ° to 100 ° C.
It takes several minutes to about 20 hours.

In 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 may be substituted, especially an alkyl group as described above. The compound, which is a substituted alkyl group in which both Y and Z are oxygen atoms, can be produced by the following three-step process.

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

[0264] reaction of this step, R ^3, compound R ⁸ and R ⁹ are both hydrogen atoms (IV _'H)

[0265]

[Chemical 47]

(Wherein 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 products can be separated by a conventional method such as column chromatography or preparative thin layer chromatography to obtain the desired compound.

The reaction in this step is usually carried out 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 include organic bases such as pyridine and triethylamine, water, and mixed solvents of these solvents.

As the base to be used, alkali metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, alkali hydroxides such as sodium hydroxide, potassium hydroxide and calcium hydroxide. Metals or alkaline earth metals, alkali metal hydrides such as sodium hydride and potassium hydride, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxy, butyllithium, tert-butyllithium and other organic lithium Examples thereof include compounds, lithium dialkylamides such as lithium diisopropylamide and lithium dicyclohexylamide, and organic bases such as pyridine and triethylamine. Preferred are alkali metal carbonates such as potassium carbonate. That.

The ratio of the starting compound (IV ′ _H ) to the alkyl halide was 1 mol of the alkyl halide to 1 mol of the starting compound.
-10 mol, and the ratio of the raw material compound to the base is 1 to 10 mol of the base per 1 mol of the raw material compound. Reaction temperature,
The reaction conditions such as the reaction time vary depending on the raw materials used, the alkyl halide and the type of solvent used, but are usually -10 to 100 ° C and several minutes to several days.

Further, the compound produced in the above reaction in which R ⁹ is a hydrogen atom is subjected to the same alkylation reaction as described above to obtain an alkyl group or a substituted alkyl group which is the same as or different from R ³ and / or R ^8. Then, the compound of interest can be obtained. The reaction conditions for this reaction are the same as those used above.

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

The second step is an optional reaction to produce a compound in which at least one of R ³ , R ⁸ and R ⁹ is an alkyl group substituted with a carboxy group or a hydroxyl group as described above. It is a process to do.

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

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

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

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

The reaction of this step is carried out in an organic solvent under anhydrous condition 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. , Preferably mineral acids 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 an optional reaction, and is 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. Is a process of manufacturing.

In the reaction of this step, the compound in which at least one of R ³ , R ⁸ and R ⁹ obtained in the second step is an alkyl group substituted with a corresponding carboxy group or hydroxyl group, It is achieved by processing according to the usual esterification reaction conditions.

In formula (I), W is a methylene group or a carbonyl group, U is a methylene group, and R ³ and R ⁸
Is a hydrogen atom, R ⁹ is an optionally substituted alkyl group described above, and Y and Z are both oxygen atoms, and is obtained by the selective alkylation reaction of the compound (IV ′ _H ) described above. be able to. The reaction conditions of this reaction are 1 to 5 mol of alkyl halide, preferably 1 to 3 mol, relative to 1 mol of the raw material compound in the above-mentioned alkylation reaction, and the reaction temperature and the reaction time are 30 minutes to 3 at 0 to 100 ° C
It's time.

In the formula (I), W is a methylene group or a carbonyl group, U is a methylene group, Y and Z are both oxygen atoms, and (a) R ⁸ is a hydrogen atom, R ³
And R ⁹ is an optionally substituted alkyl group (dialkyl substituted product) described above, or (b) R ³ ,
The compound in which R ⁸ and R ⁹ are an optionally substituted alkyl group (trialkyl substituted product) can be obtained by the selective alkylation reaction of the compound (IV ′ _H ) described above. The reaction conditions of this reaction are as follows: 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 per 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, and R ⁸ and R ^{9 are}
Is a hydrogen atom, R ³ is R ³ ′ _b [wherein R ³ ′ _b is a hydrogen atom or an acyl group excluded from the definition of R ³ , and
The substituent of the optionally substituted alkyl group represents an alkoxycarbonyl group or an acyloxy group having the same meaning as described above. And a compound (IV _a ) in which Y is both an oxygen atom, is reacted with a corresponding halogenocarboxylic acid derivative (II _a ) and thiourea as shown below, and then subjected to a hydrolysis reaction. Obtained by

[0284]

[Chemical 48]

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 above-mentioned reaction of compound (II) with thiourea and then hydrolysis reaction of the obtained 2-imino compound (III). When the solvent used in the decomposition reaction is an alcohol, when the substituent R ³ ′ _b has an ester residue, transesterification with the solvent alcohol may occur, and for example, 2-methoxyethanol is used. If
R ³ ′ _b of the target compound (IV _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.

[0288] starting compound in the present process (II _a), for example compounds of the A method described later (II) (W:> CH 2) Oh <br/> Rui compound of Method D (II) (W:> = Although it is a compound corresponding to O), compound (3 ′) or (12 ′) can be produced according to the following alkylation reaction, and can be obtained according to Method A or Method D below.

That is, in contrast to chromanes (3H) or (12H) represented by 6-hydroxy-2- (4-nitrophenoxyalkyl) chroman, A-2 described later is used.
By reacting an optionally substituted alkyl halide such as alkoxycarbonylmethyl halide as an optionally substituted alkyl halide such as methoxymethyl halide in the step, the starting material (3 ′) in the present invention Or the production of (12 ') is achieved.

[0290]

[Chemical 49]

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 above-mentioned alkylation reaction.

In formula (I), W is a hydroxymethylene 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. The compound can be obtained by reducing the compound in which W obtained by the above-mentioned alkylation reaction is a carbonyl group. The reaction conditions are the same as the above-mentioned production of compound (VIII) by reduction of compound (VII).

In formula (I), W is a> = N-OV group,
A compound in which both Y and Z are oxygen atoms and at least one of R ³ , R ⁸ and R ⁹ is an optionally substituted alkyl group is a compound in which W obtained by the above alkylation reaction is a carbonyl group. A compound of formula H ₂ N-OV
It can be obtained by reacting with a hydroxylamine derivative having the formula (V has the same meaning as described above). The reaction conditions are the compound (VI
I ') and is similar to the reaction with H ₂ N-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 may be substituted. The compound which is an alkyl group can be obtained by acylating the 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 the production of compound (XX) by acylation of compound (XVIII) described above.

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

In formula (I), W and U form a carbon-carbon double bond, both Y and Z are oxygen atoms, and R ³ ,
In a compound in which at least one of R ⁸ and R ⁹ is an optionally substituted alkyl group, W obtained by the above reaction is a hydroxymethylene group or> CH—O.
R ³ 'each water from the compound is _a group or R ^3'
It can be obtained by removing _a OH. The reaction conditions are the above-mentioned compound (VII) dehydration reaction or compound (X) R ³ ′ _a OH elimination reaction (compound (XI
It is similar to the production of I).

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 compound (XII) described above.
This is the same as the production of compound (IV) by hydrogenation of.

In formula (I), W represents a carbonyl group, and U
Is a double bond together with R ¹ , Y and Z are both oxygen atoms, R ⁸ and R ⁹ are hydrogen atoms, R ³ is R ³ ′ _b , and Y and Z are both oxygen atoms. (XV _a ) is the corresponding halogenocarboxylic acid derivative (XIII
It is obtained by reacting _a ) with thiourea and then hydrolyzing the reaction product. Raw material compound (XI
II _a ) can be produced according to the method H described below,
The reaction conditions for producing the target compound (XV _a ) are the same as those for the above-mentioned reaction of compound (XIII) with thiourea and then for production of compound (XV) by hydrolysis.

In formula (I), W represents a carbonyl group, and U
Is 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 an optionally substituted alkyl group.
^A compound in which ³ , R ⁸ and R ⁹ are both hydrogen atoms (X
V ′ _H )

[0301]

[Chemical 50]

(Wherein R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ ,
Ar and n have the same meanings as described above. ) Is reacted with an alkyl halide in the presence of a base. The reaction conditions are the compound (X
It is the same as in the case of the alkylation reaction of _V'H ).

In formula (I), W is a> = N-OV group or>
= A N-OR ³ _'a group, U together with R ¹ denotes a double bond, Y and Z are both oxygen atoms, R ^3, R
^A compound in which at least one of ⁸ and R ⁹ is a substituted alkyl group can be obtained from the compound in which W is a carbonyl group obtained by the above reaction, by the above-mentioned oximation reaction and its acylation reaction. .

R ³ , R ⁸ obtained by each of the above reactions
And a compound having an alkyl group in which at least one of R ⁹ is substituted with a carboxy group or an alkoxycarbonyl group, or a reactive derivative thereof, is subjected to an amidation reaction according to a conventional method to give substituents R ³ , R ⁸
And a compound in which at least one of R ⁹ is an alkyl group substituted with a corresponding substituted or unsubstituted carbamoyl group can be obtained.

In formula (I), W is the formula> = N-OV (wherein
V has the same meaning as described above. ) Or the formula> = N
The compounds belonging to the so-called oxime type, oxime ether type and oxime ester type which are —OR ³ ′ _a (wherein R ³ ′ _a has the same meaning as described above) are
It may be anti-form or syn-form, and 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 salt with a cation, the cation is an alkali metal ion such as sodium or potassium, Examples thereof include alkaline earth metal ions such as calcium and trivalent metal ions such as aluminum.

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

Further, in the formula (I), W is a formula> CH-O.
R ³ ′ [R ³ ′ has the same meaning as described above. ] In the thiazolidine derivative represented by the formula (I), the carbon atoms at the 2-position and 4-position of the chroman ring and the 5-position of the thiazolidine ring are asymmetric carbon atoms, and each isomer based on them is also Included in the compounds of the invention.

[0309] Also, In formula (I), W is a carbonyl group, the formula = N-OV group or the formula ^{= N-O-R 3 '} a group (wherein and R ^3' _a is as defined above. ), And U is R
^In a thiazolidine derivative showing a double bond with ¹ ,
The carbon atom at the 5-position of thiazolidine is an asymmetric carbon atom, and isomers based on it are also included in the compound of the present invention.

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

The α-halogenocarboxylic acid derivatives (II), which are the starting compounds for producing the target compound represented by the above 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). General formula (II)
In the compound W ₁ is a methylene group (II) (W _1: C
H ₂ ).

[0313]

[Chemical 51]

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 above 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, chromanes having an amino group at Ar (Ar has the same meaning as above) (4)
Is diazotized and then subjected to Meerwein Arylation, whereby production of α-halogenocarboxylic acid derivatives (II) (W: CH ₂ ) as a raw material of the target compound (I) in the present invention is achieved. To be done. The reaction is diazotized with nitrites such as sodium nitrite in the presence of hydrochloric acid, hydrobromic acid and the like, and then acrylic acid, methyl acrylate, acrylic acid esters such as ethyl acrylate and ethyl crotonic acid. , ethyl methacrylate, acrylonitrile, methacrylonitrile, acrylic acid amide of the general formula R ⁶ R such methacrylamide
⁷ C = CR ⁸ ′ A (wherein R ⁶ , R ⁷ , R ⁸ ′ and A
Has the same meaning as described above. The presence of an acrylic acid derivative represented by the formula (1) or an acrylic acid homologue (wherein R ⁶ or R ⁷ is preferably a hydrogen atom; R ⁸ ′ is preferably a hydrogen atom or a methyl group, particularly a hydrogen atom). Underneath, start by acting a catalytic amount of cuprous salts such as cuprous chloride, cuprous oxide.
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 the same as that of the compound (4).
Acrylic acid derivatives are 1 to 15 mol, preferably 5 to 10 mol per mol. The ratio of the compound (4) to the cuprous salt is 0.01 to 1 mol, and preferably 0.03 to 0.3, relative to 1 mol of the compound (4).
It is a mole. The reaction temperature and reaction time depend on the raw materials used,
Although it depends on the solvent and the like, it is usually at room temperature to 100 ° C. for about 10 minutes to about 20 hours, preferably at 40 to 60 ° C.
0 minutes to 2 hours.

Method B Method B is also advantageously used for synthesizing the compound of formula (II) wherein W is a methylene group.

[0321]

[Chemical 52]

In the chroman alcohols (2), compounds in which n is 2, are, for example, Journal of American Oil Chemistry Society Vol. 51 ,
Page 200 (1974) [J. Am. Oil Chemist's Soc., 5
1, 200 (1974)], the compound can be produced from the hydroquinone (5) in multiple steps, but according to the method disclosed in JP-A-58-201775, 1
It is also possible to manufacture in stages. In the above reaction formula, R ¹
R ² , R ³ , R ⁴ , and R ⁵ have the same meanings as described above. After that, the synthesis of α-halogenocarboxylic acid derivatives (II) (W: CH ₂ ) can be achieved by using a method including several steps in accordance with the following method of step A-2.

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

This method is described in Journal of Medicinal Chemistry, Vol. 18 , p. 934 (1975) [J. Med.
Chem., 18, 934 (1975)], wherein R ¹ ′ (R ¹ ′ at the 2-position of the chroman ring is the same as the above R ¹ except that a hydrogen atom is excluded). (Shown) can be used to advantage.

[0325]

[Chemical 53]

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 alkyl, alkenyl, alkynyl and aralkyl. The group and an optionally substituted phenyl group are preferably lower alkyl groups, 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.

[0328] C-5 C-5 process is done as required, is a step of protecting a phenolic hydroxyl group, it is preferable to protect the phenolic hydroxyl group prior to the C-6 process. 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 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 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 alkylating 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.

[0329] C-6 C-6 process, if desired, hydroxyl group protected in the chroman ring 6-position, in the step of producing a chroman-carboxylic acid derivatives (11) with R ¹ 'in the ring 2-position , Chroman ring 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 represented by 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.

[0331] The reaction temperature is-
78 ° C. to room temperature, the anion and R ¹ ′ -X ′ in the latter stage
In the reaction with, the temperature is 0 ° C. to 60 ° C., and the time required for the reaction is 30 minutes to 2 hours in the first step and 1 hour to 24 hours in the second step.

Thereafter, the production of α-halogenocarboxylic acid derivatives (II) (W: CH ₂ ) is achieved by successively using the method according to the method of the step A-1 and the following steps.

If desired, the chromancarboxylic acids (10) in which R ¹ is a hydrogen atom are used, and the reaction according to the step A-1 and the subsequent steps are directly performed without passing through the step C-6. By carrying out the reaction, α-halogenocarboxylic acid derivatives (II) in which R ¹ is a hydrogen atom (W: CH ₂ ).
Manufacturing is achieved.

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

[0335]

[Chemical 54]

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.

[0338] D-3 D-3 step is equivalent to Step A-4 described above is accomplished in the same manner as step A-4.

Method E The method E is that in the general formula (II), W is a carbonyl group,
Further, it is advantageously used for producing a compound having a substituent R ¹ ′ (R ¹ ′ has the same meaning as described above) at the 2-position of the chroman ring.

In this method, the chromone carboxylic acids (8) obtained in the above step C-3 are formed under conditions milder than those used in the step C-4 to form carbon atoms at the 2nd and 3rd positions. Reducing the double bond (E-1); and each of E-2 to E-7.

[0341]

[Chemical 55]

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

[0343] E-1 E-1 is a step of obtaining a more 4-oxo chroman carboxylic acid (14) chromone carboxylic 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.

[0344] E-2 E-2 step is 4-oxo-chroman-carboxylic acid (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 to cyclic or acyclic ketone acetals or ketone dithioacetals, and conversion to ketone dithioacetals is preferable. Chroman carboxylic acids having a protected carbonyl group (15) [wherein R ² , R ⁴ , R ⁵ , and B ₁ have the same meanings as described above, and B ₂ is of 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} - (cis), preferably of formula -
(CH ₂ ) ₂ -or formula- (CH ₂ ) ₃ --particularly formula-
(CH ₂ ) ₃ −. The production of] is usually carried out using 4-oxochromancarboxylic acid (14) and ethylene glycol, 1,3-propanediol, 1,2-ethanedithiol, 1,3-propanedithiol or cis-2.
- such as butene-1,4-diol _{H-B 3 -B 4 -B 3} -
A compound represented by H (wherein B ₃ and B ₄ have the same meanings as described above), preferably 1,3-propanedithiol, is obtained by dehydration reaction in the presence or absence of a catalyst. It Examples of the catalyst include 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; acetic acid, succinic acid, fumaric acid, maleic acid, paratoluenesulfonic acid. Examples thereof include organic acids such as methanesulfonic acid, Lewis acids are preferable, and acetic acid complex salts of boron trifluoride are particularly preferable. 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 The E-3 step 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. is there. 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
-Achieved by using an alkylating agent such as butyl or an alkylating agent such as benzyl 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.

[0346] E-4 E-4 process, as desired, hydroxyl group protected in the chroman ring 6-position, protected carbonyl group in the ring position 4, chroman carboxylic having R ¹ 'in the ring 2-position In the step of producing acids (17), 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 and lithium isopropylcyclohexylamide. Examples thereof include alkane 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 − in the generation of the anion in the preceding stage.
78 ° C. to room temperature, the anion and R ¹ ′ -X ′ in the latter stage
In the reaction with, the temperature is 0 ° C. to 60 ° C., and the time required for the reaction is 30 minutes to 2 hours in the first step and 1 hour to 24 hours in the second step.

If desired, a chromancarboxylic acid (16) in which R ¹ is a hydrogen atom is used, and the reduction reaction directly following the E-5 step and the subsequent E-5 step without directly passing through the E-4 step. By carrying out each of the indicated reactions, R ¹
Α-halogenocarboxylic acid derivatives (I
I) _{(W:> = O)} can be manufactured.

[0350] E-5 E-5 process, 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). It is preferably 1 to 2 mol with respect to 1 mol of the compound (17). 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 performed at -50 ° to 120 ° C. for about 10 minutes to about 20 hours.

[0352] E-6 E-6 process alcohols obtained in E-5 step (1
8) is a step of introducing the formula (A _r ) -NO ₂ group (wherein Ar is as defined 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 methoxide, sodium ethoxide and potassium tert-butoxide. Preferably, sodium hydride or sodium ethoxide is reacted to give compound (18) as a corresponding alkoxide, and a compound having the 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 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 protected carbonyl group at the 4-position of the chroman ring obtained in this step is
According to Method A, the α-halogenocarboxylic acid derivative is converted to the target compound (I) stepwise through a reduction reaction and a Mailbain arylation. The deprotection reaction at the 4-position of the chroman ring is one of the above. May be carried out at the stage of, for example, the process shown in E-7 can be mentioned as one of the preferable methods.

[0354] E-7 E-7 step can, if desired, hydroxyl group protected in the chroman ring 6-position, is a step of performing deprotection of the nitro compound (19) having a protected carbonyl group at the 4-position . 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, or a Lewis acid such as aluminum chloride. Acid; particularly when B ₃ is a sulfur atom, a heavy metal salt, a heavy metal oxide or a heavy metal peroxide; or a mixture of two or three of these, as the heavy metal ion, silver, cadmium, divalent mercury, Divalent copper, trivalent thallium, and the like, counter ions of heavy metal ions include halogen ions such as chlorine, bromine, and iodine, nitrate ions, and peroxide ions such as perchlorate ions. Other iodine, sulfuryl halides such as sulfuryl chloride, N such as N-chlorosuccinimide, N-bromosuccinimide
Examples thereof include haloimides, preferably mercuric chloride, mercuric oxide, 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, and 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, and is usually 1 to 10 mol, preferably 1 to 4 mol of the deprotecting agent per 1 mol of (19). Reaction temperature,
The reaction conditions such as reaction time will differ depending on the starting materials and solvent used, but are usually room temperature to 100 ° C., preferably 40 to 80 ° C., several minutes to several hours, preferably 0.5
To 4 hours.

Thereafter, the production of the α-halogenocarboxylic acid derivatives (II) _{(W:> = O)} is achieved by successively using the method according to the method of the step D-2 and the following steps.

Method F Method F is for preparing 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 to advantage.

[0359]

[Chemical 56]

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

F-1 In the F-1 step, the 4-oxochroman compound (12) having a nitro group is converted to 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 of compound (12) with sodium borohydride is usually carried out in a solvent. As the solvent,
Examples thereof 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). Preferably compound (12) 1
It is 1 to 20 moles per mole. 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 produced, 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 carried out 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 the acylating agent in a slight excess over equimolar amount to the compound (21). The amount of the acylating agent is preferably 1 to 10 mol, based on 1 mol of the compound (21). The reaction conditions such as reaction temperature and reaction time are usually 0 to 100 ° C., though they vary depending on the raw materials used and the type of solvent used.
It takes 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. As the dehydrating agent or dehydrating catalyst, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, organic acid salts such as acetic acid, succinic acid, maleic acid, paratoluenesulfonic acid, naphthalenesulfonic acid,
Examples include sulfonic acids such as methane sulfonic acid, inorganic salts such as ammonium chloride and calcium chloride, phosphorus pentoxide, polyphosphoric acid, silica gel, alumina, etc., but organic acids such as acetic acid, sulfonic acids such as paratoluene sulfonic acid, etc. It is suitable.

In the elimination reaction, a solvent may not be used, but when a solvent is used, alcohols such as methanol, ethanol and isopropanol, acetone, ketones such as methyl ethyl ketone, ether, Tetrahydrofuran, ethers such as dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane, cyclohexane and heptane, halogenated hydrocarbons such as dichloromethane and chloroform, acetic acid , Organic acids such as propionic acid, pyridine, organic bases such as triethylamine, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, sulfones such as sulfolane, and water. Preferably Organic acids such as aromatic hydrocarbons or acetic acid such as Zen and the like. 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 used per 1 mol of the compound (21). Is 0.01 to 10 mol, preferably 0.1
To 3 moles. 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 they are generally 0 to 100 ° C., and several minutes to about 20 hours.

[0369] F-4 F-4 process, from having a nitro group 4 acyloxyalkyl chroman compound (23), 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. As a deoxidizing agent or dehydration catalyst, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, organic acids such as acetic acid, succinic acid, maleic acid, paratoluenesulfonic acid, naphthalenesulfonic acid,
Examples thereof include sulfonic acids such as methanesulfonic acid, inorganic salts such as ammonium chloride and calcium chloride, organic bases such as pyridine and triethylamine, silica gel, alumina, and the like, preferably organic acids such as acetic acid and para. Examples thereof include sulfonic acids such as toluene sulfonic acid.

A solvent may not be used in the deoxidation reaction, but when a solvent is used, alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, and ethers are used. , 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 acids such as acetic acid and propionic acid, organic bases such as pyridine and triethylamine, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, sulfones such as sulfolane, and water. , Preferably Aromatic hydrocarbons such as benzene, or organic acids such as acetic acid.

When a deoxidizing agent or a deoxidizing catalyst is used, the ratio of the compound (23) to the deoxidizing agent or the deoxidizing catalyst is not particularly limited, but it is usually 1 mol of the compound (23). The deoxidizing agent or deoxidizing catalyst is 0.01 mol to 10 mol, 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 10 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. The catalyst used for catalytic reduction is palladium-carbon,
Raney-nickel, platinum oxide and the like can be mentioned, but palladium-carbon is preferable. Hydrogen pressure is 1 atm to 1
The pressure is 00 atm, but 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 of these. 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.

Incidentally, F-1, F-2, F-3, F-4,
The final steps of producing F-5, A-4 and / or the desired thiazolidine derivative are sequentially, if desired, intermediates (21), (22), (23), (4) and / or (II ) (W ₁ : CH ₂ ) can be carried out without isolation.

The steps shown in, for example, 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, and then 4
The reduction of the carbonyl group at the position and further dehydration to give a 2H-chromene derivative, and subsequent reduction of the double bond to give the amino compound (4) are the same as in Method F.

Method G Method G is similar to method F and is used for preparing a compound of the general 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. You can That is, B ₂ produced by the deprotection reaction of the protecting group for the hydroxyl group at the 6-position of the chroman ring and the acylation reaction of the hydroxyl group described in Method D, Method E, and Method A is represented by the formula —S— (CH ₂ )
_{When the} compound (24) or (26) showing a _p -S-group (wherein p is 2,3,4) is catalytically reduced by a nickel catalyst such as Raney-nickel, the 4-position of the chroman ring is a methylene group. A compound (25) or (27) can be obtained, respectively.

[0379]

[Chemical 57]

The hydrogen pressure in this reaction is 1 atm to 100 atm, preferably 1 atm to 6 atm. As a solvent,
Examples thereof 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 mixtures 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.

Method H The method H is a precursor of the above-mentioned compound (XV) in which, among the target compounds represented by the formula (I), W represents a carbonyl group and U represents a methylene group or a double bond together with R ^1. Body, that is, it can be used for producing α-halogenocarboxylic acid derivatives (XIII) in which the 2-position of the chroman ring is L (L has the same meaning as described above).

[0382]

[Chemical 58]

In the formula, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and 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, a double bond can be formed between L and U. Compound (28) has the formula O ₂ N- (Ar) -O- (CH ₂ ).
A compound having _n- COX (wherein Ar, n and X have the same meanings as described above) is reacted and then given by treatment with an organic base such as sodium ethoxide and potassium t-butoxide. To be

H-2 The H-2 step is the same as the A-3 step, and the relationship between L and U is the same as the description of H-1.

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

Among the production methods of the raw material compounds, that is, the α-halogenocarboxylic acids (II) by the Method A to Method H, the preferable ones are Method A, B, C, D, E, F and H, and , A, C, D, E, F and H methods.
It is more preferable to use the method D, the method F, and the method A in combination.

In the α-halogenocarboxylic acids represented by the formula (II), α of the chroman ring 2-position and the substituent A is
Each carbon atom at position is an asymmetric carbon atom, and each isomer based on them is also included in compound (II).

The α-halogenocarboxylic acid derivatives (II) thus obtained were also found to have not only blood lipid-lowering activity but also blood triglyceride and cholesterol-lowering activity. Therefore, it is useful as a therapeutic agent for hyperlipidemia.

Α-containing the chroman ring thus obtained
If desired, halogenocarboxylic acid derivatives (II) can be converted into various hydrolysis products, transesterification products, or metal salts such as sodium, potassium, calcium, and aluminum, or vice versa. Alternatively, free phenols and / or free carboxylic acids can be converted into an ester form, an amide form and the like.

In particular, when the α-halogenocarboxylic acid derivatives (II) are converted into desired various hydrolytic products,
The production of the grade is achieved as follows, for example.

A compound in which R ³ is a hydrogen atom and A is a carboxy group can be prepared by reacting a compound (II) in which R ³ is, for example, an acyl group and A is an alkoxycarbonyl group with an alkali metal such as sodium carbonate or potassium carbonate. Inorganic bases such as carbonates, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, or sodium methoxide,
It can be obtained by carrying out a hydrolysis reaction in the presence of a base such as an alkali metal alcoholate such as sodium ethoxide and potassium tert-butoxide. Examples of the solvent include lower alcohols such as methanol and ethanol, tetrahydrofuran,
Examples thereof include ethers such as dioxane, water and a mixed solvent thereof. The ratio of the compound (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). 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 several minutes to tens of hours.

Compounds in which R ³ is a hydrogen atom and A is an alkoxycarbonyl group can be used in the case where R ³ is, for example, an acyl group or A
Compound (II) in which is an alkoxycarbonyl group can be obtained by carrying out a solvolysis reaction in the presence of a base such as an alkali metal alcoholate such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide. . As the solvent, methanol, ethanol, propanol, isopropanol,
Examples thereof include alcohols such as t-butyl alcohol, ethers such as tetrahydrofuran and dioxane, and mixed solvents 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 is changed to
It 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).
Is. 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 an acyl group and A is a carboxy group can be prepared by reacting a compound (II) in which R ³ is an acyl group and A is an alkoxycarbonyl group with an alkali metal such as sodium carbonate or potassium carbonate. Inorganic bases such as carbonates, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, or sodium methoxide,
It can be obtained by carrying out a hydrolysis reaction in the presence of a base such as an alkali metal alcoholate such as sodium ethoxide and potassium tert-butoxide. Examples of the solvent include lower alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, water, and mixed solvents thereof. The compound (II) and the inorganic base,
Alternatively, the ratio with 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, bases, solvents, etc. used, but usually the reaction temperature is -10 to 30 ° C, preferably 0 to 10 ° C, and the reaction time is a few minutes to about 10 hours. is there.

Preferred compounds represented by the formula (II) which exhibit the above-mentioned pharmacological activity include the thirteenth compounds having the following structural formulas.
The compounds shown in the table can be mentioned.

[0396]

[Chemical 59]

[0397]

[Table 105]

[0398]

[Table 106]

[0399]

[Table 107]

[0400]

[Table 108]

[0401]

[Table 109]

[0402]

[Table 110]

[0403]

[Table 111]

[0404]

[Table 112]

[0405]

[Table 113]

[0406]

[Table 114]

[0407]

[Table 115]

[0408]

[Table 116]

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

[0410]

[Chemical 60]

[0411]

[Table 117]

[0412]

[Table 118]

[0413]

[Table 119]

[0414]

[Table 120]

[0415]

[Table 121]

[0416]

The object compound of the present invention represented by the above-mentioned general formula (I) has a high antioxidant action against unsaturated fatty acids such as linoleic acid and ethyl linoleate and their esters, and therefore, in vivo. It is expected to be able to prevent the oxidation of phospholipids with a high percentage of unsaturated fatty acids;
Biochem.Biophys.Res.Commun, 95 , 734-737.
In the rat liver microsomal lipid peroxidation inhibition test shown in (1980), not only it has a strong lipid peroxidation-lowering effect but also blood peroxidation in the test of experimental hyperlipidemic mice induced by alloxan. Lowers lipids, triglycerides and cholesterol,
It has a hypoglycemic effect in the test of genetically hyperglycemic KK mice, and in the test of aldose reductase activity measurement using a bovine lens, it shows an extremely excellent pharmacological effect such as showing an enzyme inhibitory effect, Concerning toxicity, it is a compound having extremely low appetite-reducing action, weight-gain suppressing action, and especially hepatomegaly action on experimental animals such as rats.

From the results of the above tests, the thiazolidine derivative (I) of the present invention is useful for the treatment of human hyperlipidemia, diabetes and their complications such as diabetic cataract and diabetic neuropathy. Be expected. The administration method is, for example, orally used as tablets, capsules, powders, granules and the like, as well as injections (intravenous, subcutaneous, intramuscular),
It can be administered parenterally as a suppository, and as an ocular mucosal administration, an eye drop and an eye ointment are preferable. The dose varies depending on the 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.

[0418]

EXAMPLES The present invention will be described more specifically with reference to Examples, Production Examples (compounds in which R ⁹ is a hydrogen atom) and Reference Examples.

Production Example 1 5- [4- (6-acetoxy-5,7,8-trimethyl]
-2-octylchroman-2-ylmethoxy) benz
Le] thiazolidine-2,4-dione ethyl 3- [4- (6-acetoxy -5,7,8- trimethyl-2-octyl-chroman-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 of silica gel thin layer chromatography
Value = 0.55 (developing solvent; benzene: ethyl acetate = 4:
1).

NMR spectrum (δ ppm, CDC
l 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 = 6H
z), 3.03 (1H, dd, J = 10 and 15Hz), 3.44 (1H, dd, J = 3 and
15Hz), 3.92 (2H, s), 4.45 (1H, dd, J = 3 and 10Hz), 6.85 (2
H, d, J = 9Hz), 7.13 (2H, d, J = 9Hz), 8.0-8.9 (1H, br., Disappeared by adding heavy water).

Production Example 2 5- [4- (6-acetoxy-5,7,8-trimethyl]
-2-octylchroman-2-ylmethoxy) benz
]]-Iminothiazolidin-4- one In silica gel column chromatography in Production Example 1, a portion eluted after the thiazolidine-2,4-dione (eluent; benzene: tetrahydrofuran =
The target compound (white powder) was obtained from 4: 1).

Softening point: 85-90 ° C. NMR spectrum (δ ppm, 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 = 10 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 = 9Hz)
.

Production Example 3 5- [4- (6-hydroxy-5,7,8-trimethyl]
-2-octylchroman-2-ylmethoxy) benz
Le] thiazolidine-2,4-dione ethyl 3- [4- (6-acetoxy -5,7,8- trimethyl-2-octyl-chroman-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. Then, 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 85-
Heat further at 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 obtain the target compound (pale yellow foamy solid).

Rf of silica gel thin layer chromatography
Value = 0.43 (tailing) (developing solvent; benzene: ethyl acetate = 4: 1) NMR spectrum (δ ppm, CDCl ₃ ): 0.7-1.0
(3H, m), 1.1-2.1 (16H, m), 2.10 (6H, s), 2.15 (3H, s), 2.61 (2
H, br.t, 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 = 9H)
z), 7.13 (2H, d, J = 9Hz), 8.33 (1H, br.s, disappeared by addition of heavy water).

Production Example 4 5- [4- [6-acetoxy-2-methyl-7- (1,
1,3,3-Tetramethylbutyl) chroman-2-yl
Methoxy] benzyl] thiazolidine-2,4-dione Ethyl 3- [4- [6-acetoxy-2-methyl-7- (1,1,3,3-tetramethylbutyl) chroman-2 according to Preparation Example 1 -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 (δ ppm, CDCl ₃ ): 0.79 (9H, 9H,
s), 1.36 (6H, s), 1.45 (3H, s), 1.66-2.28 (2H, nd), 1.80 (2H,
s), 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, b
r., disappeared by adding heavy water).

Production Example 5 5- [4- [6-acetoxy-2-methyl-7- (1,
1,3,3-Tetramethylbutyl) chroman-2-yl
Methoxy] benzyl] -2-iminothiazolidine-4-
According to on- production example 2, 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.

Melting point: 120-128 ° C. NMR spectrum (δ ppm, deuterated acetone): 0.78 (9H,
s), 1.35 (6H, s), 1.41 (3H, s), 1.82 (2H, s), 1.90-2.17 (2H, n
d), 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, d
d, 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).

Production Example 6 5- [4- [6-hydroxy-2-methyl-7- (1,
1,3,3-Tetramethylbutyl) chroman-2-yl
Methoxy] benzyl] thiazolidine-2,4-dione Ethyl 3- [4- [6-acetoxy-2-methyl-7- (1,1,3,3-tetramethylbutyl) chroman-2 according to Production Example 3 -Ylmethoxy] phenyl] -2-
The target product produced 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, 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,
dd, J = 4 and 14Hz), 3.93 (2H, AB type, J = 9Hz), 4.45 (1H, s, disappears by adding 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).

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

Softening point: 80-88 ° C. (pale yellow powder) NMR spectrum (δ ppm, CDCl ₃ ): 0.78 (9H,
s), 1.37 (6H, s), 1.53 (3H, s), 1.83 (2H, s), 2.30 (3H, s), 2.7
0 (1H, d, J = 17Hz), 2.8-3.2 (1H, nd), 3.10 (1H, d, J = 17Hz), 3.
45 (1H, dd, J = 4 and 15Hz), 4.00 and 4.12 (2H, AB type, J = 9
Hz), 4.48 (1H, dd, J = 4 and 9Hz), 6.85 (2H, d, J = 9Hz), 7.02
(1H, s), 7.17 (2H, d, J = 9Hz), 7.51 (1H, s), 8.3-9.0 (1H, br.,
It disappears when heavy water is added).

Production Example 8 5- [4- [6-acetoxy-2-methyl-4-oxo]
-7- (1,1,3,3-tetramethylbutyl) chroma
N-2-ylmethoxy] benzyl] -2-iminothiazo
Lysin-4-one According to Production Example 2, ethyl 3- [4- [6-acetoxy-2-methyl-4-oxo-7- (1,1,3,3-
The target product produced from 7.3 g of tetramethylbutyl) chroman-2-ylmethoxy] phenyl] -2-chloropropionate, 1.3 g of thiourea, and 8 ml of sulfolane has the following physical properties.

Melting point: 125-130 ° C. NMR spectrum (δ ppm, 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.
40 (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 (2H, d,
J = 9Hz), 7.46 (1H, s), 7.8-8.7 (2H, br., Disappeared by adding heavy water).

Production Example 9 5- [4- [6-hydroxy-2-methyl-4-oxo
-7- (1,1,3,3-tetramethylbutyl) chroma
N-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 ethylene glycol monomethyl ether,
Heat in a nitrogen atmosphere at 85 to 90 ° C. for 6 hours. The reaction mixture is poured into water and 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 = 4: 1) to obtain the target compound (pale yellow foamy solid).

Softening point: 100-105 ° C. NMR spectrum (δ ppm, CDCl ₃ ): 0.77 (9H,
s), 1.43 (6H, s), 1.52 (3H, s), 2.00 (2H, s), 2.70 (1H, d, J = 17
Hz), 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 (1
H, dd, J = 4 and 9Hz), 6.1 (1H, br.s, disappeared by adding 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).

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

Softening point: 41-45 ° C. (pale yellow powder) NMR spectrum (δ ppm, CDCl ₃ ): 0.85 (9H, 9H,
d, J = 7Hz), 1.0-2.0 (12H, m), 2.13 (3H, s), 2.22 (3H, s), 2.55
(3H, 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., Disappeared 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).

Production Example 11 5- [2- (6-hydroxy-2,5,7,8-tetra
Methylchroman-2-ylmethoxy) pyridin-5-i
Lumethyl] thiazolidine-2,4-dione In accordance with Preparation Example 3, ethyl 3- [2- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) pyridin-5-yl]- 2-chloropropionate 3.8 g, thiourea 0.77 g, sulfolane 5.
0 ml, ethylene glycol monomethyl ether 4.5
The desired product was obtained from ml, concentrated hydrochloric acid 1.5 ml and water 4.5 ml.

Softening point: 87-94 ° C. NMR spectrum (δ ppm, CDCl ₃ ): 1.38 (3H,
s), 1.7-2.3 (2H, m), 2.06 (3H, s), 2.09 (3H, s), 2.14 (3H, s),
2.63 (2H, br.t, J = 6Hz), 3.10 (1H, dd, J = 15 and 7.5Hz),
3.33 (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).

Production Example 12 5- [3- (7-t-butyl-6-hydroxy-2-me]
Tyl-4-oxochroman-2-ylmethoxy) -4-
Methylbenzyl ] thiazolidine-2,4-dione In accordance with Preparation 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 (1
H, dd, 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, disappears 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).

Production Example 13 5- [4- (6-hydroxy-5,7,8-trimethyl]
Chromon-2-ylmethoxy) benzyl] thiazolidine
2,3,4 -dione According to Production Example 3, ethyl 3- [4- (6-acetoxy-2-hydroxy-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy) phenyl] -2-chloro The target compound was obtained from 2.2 g of propionate, 0.8 g of thiourea, 4.5 g of sulfolane, 70 ml of ethylene glycol monomethyl ether, 8 ml of water, and 4 ml of 35% hydrochloric acid.

Melting point: 249-252 ° C. NMR spectrum (δ ppm, DMSO-d ₆ ): 2.25
(6H, 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 addition of heavy water).

Production Example 14 5- [4- (6-hydroxy-2,5,7,8-tetra
Methylchroman-2-ylmethoxy) benzyl] -5-
Methylthiazolidine-2,4-dione In accordance with Preparation Example 3, ethyl 3- [4- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] -2-chloro-2 -Methyl propionate 1.17 g, thiourea 0.63 g, sulfolane 3 g, ethylene glycol monomethyl ether 10 m
The target compound produced from 1, 3 ml of water and 2 ml of 35% hydrochloric acid has the following physical properties.

Softening point: 69-72 ° C. NMR spectrum (δ ppm, 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 (1H, br.s, disappeared by adding heavy water).

Production Example 15 5- [4- (6-hydroxy-4- (E) -hydroxy]
Imino-2,5,7,8-tetramethylchroman-2-
Ilmethoxy) benzyl] thiazolidine-2,4-dio
D Method of down the then prepared in the same methods as in Production Example 1 5- [4- (6-hydroxy-2,5,7,8-tetramethyl-4-Okisokuroman-2-ylmethoxy) benzyl] thiazolidine -2,4-dione 5g, hydroxylamine hydrochloride 3g, methanol 50g 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 subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 1: 1) to obtain the target compound.

Softening point: 84-100 ° C. NMR spectrum (δ ppm, 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 = 14
Hz), 4.05 (2H, s), 4.72 (1H, dd, J = 4 and J = 9Hz), 6.92 (2
H, d, J = 9Hz), 7.21 (2H, d, J = 9Hz), 9.7-10.5 (1H, br.s, disappeared by adding heavy water).

Production Example 16 5- [4- (6-hydroxy-4- (E) -hydroxy]
Imino-2,5,7,8-tetramethylchroman-2-
Ilmethoxy) benzyl] thiazolidine-2,4-dio
Emissions 5- [4- (6-hydroxy-4-(Z) - hydroxyimino-2,5,7,8-tetramethyl-chroman-2-
62 mg of ilmethoxy) benzyl] thiazolidine-2,4-dione was 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 Production Example 15).

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

Softening point: 100-105 ° C. NMR spectrum (δ ppm, heavy acetone): 1.46 (3H,
s), 2.04 (3H, s), 2.18 (6H, s), 2.58 (1H, d, J = 13Hz), 2.87 (1
H, d, J = 13Hz), 3.10 (1H, dd, J = 9 and 14Hz), 3.43 (1H, dd,
J = 4 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 (1H, b
rs, disappeared by adding heavy water).

Production Example 18 5- [4- (6-hydroxy-4- (Z) -hydroxy]
Imino-2,5,7,8-tetramethylchroman-2-
Ilmethoxy) benzyl] thiazolidine-2,4-dio
Emissions 5- [4- (6-hydroxy-4-(E) - hydroxyimino-2,5,7,8-tetramethyl-chroman-2-
27 mg of ilmethoxy) benzyl] thiazolidine-2,4-dione was 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 Production Example 17).

Production Example 19 5- [4- (6-acetoxy-4- (E) -acetoxy]
Imino-2,5,7,8-tetramethylchroman-2-
Ilmethoxy) benzyl] thiazolidine-2,4-dio
Emissions 5- [4- (6-hydroxy-4-(E) - hydroxyimino-2,5,7,8-tetramethyl-chroman-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, and the residue was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 4: 1) to obtain the target compound.

Softening point: 93-97 ° C. NMR spectrum (δ ppm, CDCl ₃ ): 1.48 (3H,
s), 2.07 (3H, s), 2.10 (3H, s), 2.22 (3H, s), 2.33 (3H, s), 2.4
2 (3H, 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 (2
H, d, J = 9Hz), 7.14 (2H, d, J = 9Hz).

Production Example 20 5- [4- (6-benzoyloxy-4- (E) -ben
Zoyloxyimino-2,5,7,8-tetramethyl chloride
Roman-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 methoxy) 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 to 80 ° C. for 8 hours. A potassium carbonate water bath and ethyl acetate 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 = 4: 3) to obtain the target compound.

Softening point: 101-107 ° C. NMR spectrum (δ ppm, CDCl ₃ ): 1.55 (3H,
s), 2.14 (6H, s), 2.58 (3H, s), 2.8-3.7 (4H, nd), 3.98 and
4.12 (2H, AB type, J = 9Hz), 4.45 (1H, dd, J = 4 and 9Hz), 6.84
(2H, d, J = 9Hz), 7.14 (2H, d, J = 9Hz), 7.3-7.8 (6H, m), 7.9-8.
5 (4H, m).

Production Example 21 5- [4- (2,5,7,8-tetramethyl-6-nico
Tinoyloxy-4- (E) -nicotinoyloxyimi
Nochroman-2-ylmethoxy) benzyl] thiazolidi
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 to 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 evaporated, the residue was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 2: 3), and further preparative thin layer silica gel chromatography (developing solvent; hexane: ethyl acetate = 1: 10). The target compound was obtained.

Softening point: 123-130 ° C. NMR spectrum (δ ppm, CDCl ₃ ): 1.56 (3H,
s), 2.13 (3H, s), 2.17 (3H, s), 2.57 (3H, s), 2.8-3.7 (4H, n
d), 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), 1
0-11 (1H, br., Disappeared by addition of heavy water).

Production Example 22 5- [4- (7-t-butyl-6-hydroxy-4-]
(E) -Hydroxyimino-2-methylchroman-2-
Ilmethoxy) benzyl] thiazolidine-2,4-dio
In accordance with Preparation Example 15, 5- [4- (7-t-butyl-6
-Hydroxy-2-methyl-4-oxochroman-2-
The target compound (colorless crystals) produced 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 (δ ppm, heavy acetone): 1.40 (12
H, 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 = 4 and 9Hz), 6.73 (1H,
s), 6.95 (2H, d, J = 9Hz), 7.2-8.5 (1H, br., disappeared by adding heavy water), 7.25 (2H, d, J = 9Hz), 7.30 (1H, s), 9.7-10.6 (1H, br., Disappeared by adding heavy water).

Production Example 23 5- [4- [6-hydroxy-4- (E) -hydroxy]
Imino-2-methyl-7- (1,1,3,3-tetrame
Tylbutyl) chroman-2-ylmethoxy] benzyl]
Thiazolidine-2,4-dione According to Production 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 produced from 0.3 g and 10 ml of methanol has the following physical properties.

Softening point: 115-120 ° C. (white powder) NMR spectrum (δ ppm, 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
(1H, dd, J = 4 and 15Hz), 4.03 (2H, s), 4.76 (1H, dd, J = 4 and J = 9Hz), 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).

Production Example 24 5- [4- (6-hydroxy-4- (E) -hydroxy]
Imino-2-isobutyl-5,7,8-trimethylchloro
Man-2-ylmethoxy) benzyl] thiazolidine-
2,4-dione According to Production 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 6
The target product produced from 00 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, dd, J =
4 and 9Hz), 6.91 (2H, d, J = 9Hz), 7.22 (2H, d, J = 9Hz), 9.8
-10.5 (1H, br.s, disappeared by adding heavy water).

Production Example 25 5- [4- [2- (3,7-dimethyloctyl) -6-
Hydroxy-4- (E) -hydroxyimino-5,7,
8-Trimethylchroman-2-ylmethoxy] benz
Lu] thiazolidine-2,4-dione According to Production Example 15, 5- [4- [2- (3,7-dimethyloctyl) -6-hydroxy-5,7,8-trimethyl-4-oxochroman-2] The target compound prepared from 150 mg of -ylmethoxy] benzyl] thiazolidine-2,4-dione, 36 mg of hydroxylamine hydrochloride, 41 mg of pyridine and 2 ml of methanol has the following physical properties.

Softening point: 55-60 ° C. (pale yellow powder) NMR spectrum (δ ppm, CDCl ₃ ): 0.83 (9H,
d, J = 7Hz), 1.0-2.0 (12H, m), 2.10 (3H, s), 2.18 (3H, s), 2.41
(3H, 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, nd),
4.46 (1H, dd, J = 4 and 10Hz), 6.83 (2H, d, J = 9Hz), 7.15 (2
H, d, J = 9Hz), 7.8-8.9 (2H, br., Disappeared by adding heavy water).

Production Example 26 5- [4- (6-hydroxy-2,5,7,8-tetra
Methyl-4- (E) -methoxyiminochroman-2-i
Lumethoxy) 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 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 (δ ppm, CDCl ₃ ): 1.41 (3H,
s), 2.08 (3H, s), 2.17 (3H, s), 2.50 (3H, s), 2.88 and 3.08
(2H, AB type, J = 17Hz), 3.00 (1H, dd, J = 9 and 14Hz), 3.42 (1
H, 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 = 9H
z), 7.12 (2H, d, J = 9Hz).

Production 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-Okisokuroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 1g, benzyloxy hydrochloride 1.2g 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 (δ ppm, CDCl ₃ ): 1.40 (3H,
s), 2.06 (3H, s), 2.16 (3H, s), 2.41 (3H, s), 2.92 and 3.18
(2H, AB type, J = 17Hz), 3.02 (1H, dd, J = 9 and 14Hz), 3.42 (1
H, 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 = 9H
z), 7.2-7.5 (5H, m).

Production Example 28 5- [4- (4- (E) -t-butoxycarbonylmetho]
Xiimino-6-hydroxy-2,5,7,8-tetra
Methylchroman-2-ylmethoxy) benzyl] thiazo
Lysine-2,4-dione 5- [4- (6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 1 g, t-butoxy A mixture of carbonylmethoxyamine / p-toluenesulfonate (2.1 g), methanol (5 g) and pyridine (0.6 g) 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 (δ ppm, CDCl ₃ ): 1.44 (3H,
s), 1.49 (9H, s), 2.07 (3H, s), 2.17 (3H, s), 2.43 (3H, s), 3.0
2 (1H, 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 9Hz), 4.57 (2H, s), 4.9-6.1 (2H, br., Disappeared by adding heavy water), 6.84 (2H, d, J = 9Hz), 7.10 (2H, d, J = 9Hz).

Production Example 29 5- [4- (6-hydroxy-2,5,7,8-tetra
Methyl-2H-chromen-2-ylmethoxy) benz
Lu] 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: 173 to 176 ° C. NMR spectrum (δ ppm, 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 (2H, d, J = 9H
z), 7.19 (2H, d, J = 9Hz).

Production Example 30 2- [4- (2,4-dioxothiazolidin-5-yl]
Methyl) phenoxymethyl] -2,5,7,8-tetra
Methylchroman-6-ylhydrogen succinate 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2) prepared in the same manner as in the above Method A and then in Preparation Example 1 -Ylmethoxy) benzyl] thiazolidine-2,4-dione 1.0 g, succinic anhydride 0.3
A mixture of 1 g and 1 ml of pyridine was left at room temperature overnight. The reaction mixture was washed 3 times with 10 ml of cyclohexane, and the resulting insoluble matter was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 5: 1 to 1: 1).
Then, the target compound was obtained.

Melting point: 197-202 ° C. NMR spectrum (δ ppm, 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 15H
z), 3.95 and 4.05 (2H, AB type, J = 9Hz), 4.90 (1H, dd, J = 4 and 9Hz), 6.98 (2H, d, J = 9Hz), 7.30 (2H, d, J = 9Hz) ).

Sodium salt 246 mg of the present 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 Production Example 31 5- [4- (4-Carboxymethoxyimino-6- hydride]
Roxy-2,5,7,8-tetramethylchroman-2-
Ilmethoxy) benzyl] thiazolidine-2,4-dio
5- [4- (4-t-butoxycarbonylmethoxyimino-6-hydroxy-2,5, obtained in Production Example 28]
7,8-Tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 0.7 g and 4N
A mixture of 7 ml of hydrogen chloride dioxane solution was added at room temperature to
Leave for 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 (δ ppm, DMSO-d ₆ ): 1.33
(3H, s), 1.98 (3H, s), 2.09 (3H, s), 2.34 (3H, s), 2.9-3.5 (2
H, m), 3.0 (2H, s), 4.02 (2H, s), 4.65 (2H, s), 4.84 (1H, 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 addition of heavy water).

Production Example 32 2- [4- (2,4- dioxothiazolidin -5-yl]
Methyl) phenoxymethyl] -2,5,7,8-tetra
Methyl-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 added at 120 to 130 ° C. under a nitrogen stream at 5 ° C.
Heated for hours. 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, b
r.).

Production Example 33 5- [4- (6-ethoxy-2,5,7,8-tetrame
Tylchroman-2-ylmethoxy) benzyl] thiazoli
Zin-2,4-dione According to Production Example 32, 2-chloro-3- [4- (6-ethoxy-2,5,7,8-tetramethylchroman-2-
Ilemethoxy) phenyl] ethyl propionate 5.1
g, thiourea 1g, sulfolane 6ml, 2N hydrochloric acid 16m
The desired compound was obtained from 1 and 5 ml of 2-methoxyethanol.

Melting point: 56-60 ° C. Mass spectrum (m / e): 469 (M ⁺ ) NMR spectrum (δ ppm, CDCl ₃ ): 1.39 (3H,
t, J = 7Hz), 1.41 (3H, s), 1.7-2.1 (2H, nd), 2.07 (3H, s), 2.14
(3H, 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 (2H,
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).

Production Example 34 2- [4- (2,4-dioxothiazolidin-5-yl]
Methyl) phenoxymethyl] -4-hydroxy-2,
5,7,8-Tetramethylchroman-6-yloxy vinegar
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 ⁺ ) Production Example 35 2- [4- (2,4-dioxothiazolidin-5-yl)
Methyl) phenoxymethyl] -2,5,7,8-tetra
Methyl-2H-chromen-6-yloxyacetic acid methyl 2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -4-hydroxy-2,
970 mg of 2-methoxyethyl 5,7,8-tetramethylchroman-6-yloxyacetate, 50 mg of p-toluenesulfonic acid, 10 ml of benzene, and dioxane 1
The mixture of ml was heated under reflux for 1 hour under a nitrogen stream. The reaction mixture was washed with 5% aqueous sodium bicarbonate solution, then 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;
Benzene: ethyl acetate = 7: 3) to give the title methyl ester.

Rf value = 0.74 (developing solvent; benzene:
Ethyl acetate = 1: 1) NMR spectrum (δ ppm, 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 = 4 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 = 9H
z), 7.20 (2H, d, J = 9Hz).

Production Example 36 2- [4- (2,4-dioxothiazolidin-5-yl]
Methyl) phenoxymethyl] -2,5,7,8-tetra
Methyl-2H-chromen-6-yloxyacetic acid 2-meth
In the column chromatography of Production Example 35 of xyethyl , 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 (δppm, 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 = 1
0Hz), 6.88 (2H, d, J = 9Hz), 7.21 (2H, d, J = 9Hz).

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

Rf value: 0.44 (developing solvent; benzene:
Ethyl acetate = 1: 1) NMR spectrum (δ ppm, deuterated 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 (4H,
m), 4.03 (2H, s), 4.74 (1H, dd, J = 4 and 9Hz), 5.78 (1H, d, J
= 10Hz), 6.71 (1H, d, J = 10Hz), 6.88 (2H, d, J = 9Hz), 7.21 (2H,
d, J = 9 Hz).

Production Example 38 2- [4- (2,4-dioxothiazolidin-5-yl
Methyl) phenoxymethyl] -2,5,7,8-tetra
Methylchroman-6-yloxyacetic acid 2-methoxyethyl
Le 2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] 2,5,7,8-tetramethyl--2H- chromen-6-yloxy acetic acid 2-methoxyethyl 260 mg, 10% Palladium carbon 300m
The mixture of g and 50 ml of ethanol was shaken for 10 hours at a hydrogen pressure of 3 to 5 atm using a Parr hydrogenation device.
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).

Production Example 39 5- [4- [6- (2-hydroxyethoxy) -2,
5,7,8-Tetramethylchroman-2-ylmethoxy
[Ci] benzyl] thiazolidine-2,4-dione According to Production 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),
3.44 (1H, dd, J = 4 and 14Hz), 3.7-4.1 (6H, m), 4.47 (1H, d
d, J = 4 and 9Hz), 4.8-5.2 (2H, br), 6.87 (2H, d, J = 9Hz), 7.
14 (2H, d, J = 9Hz).

Production Example 40 2- [4- (2,4-dioxothiazolidin-5-yl]
Methyl) phenoxymethyl] -2,5,7,8-tetra
Methyl-4-oxochroman-6-yloxyacetic acid ethyl
Obtained in Le Preparation 44, 2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl]
A mixture of 0.5 g of 2,2,5,7,8-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:
This was attached to 3) to obtain the target compound.

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 = 9Hz), 7.16 (2
H, d, J = 9Hz), 8.3-8.9 (1H, br.).

Example 1 5- [4- (6-acetoxy-2,5,7,8-tetra
Methylchroman-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 acetone (8 ml) was added dropwise t-butyl bromoacetate (0.87 g) under ice-cooling, the mixture was stirred at room temperature for 2 hr, and left for 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 distilled off, 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 = 10: 1) NMR spectrum (δ ppm, 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, dd, J = 10 and 14Hz), 3.55 (1H, dd, J = 4 and 14Hz),
3.86 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 = 9H
z).

Example 2 5- [4- (6-acetoxy-2,5,7,8-tetra
Methylchroman-2-ylmethoxy) benzyl] -2,
4-Dioxothiazolidine-3-methyl acetate According to 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 and 25 ml of acetone.

Rf value: 0.26 (developing solvent; benzene:
Ethyl acetate = 20: 1) NMR spectrum (δppm, 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
(1H, dd, J = 4.5 and 10Hz), 6.89 (2H, d, J = 9Hz), 7.17 (2H,
d, J = 9Hz).

Example 3 5- [4- (6-hydroxy-2,5,7,8-tetra
Methylchroman-2-ylmethoxy) benzyl] -2,
4-Dioxothiazolidine-3-t-butyl acetate According to 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 (δppm, 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 14H
z), 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 = 9Hz).

Example 4 5- [4- (6-t-butoxycarbonylmethoxy-
2,5,7,8-Tetramethylchroman-2-ylmeth
Xy) 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 (2
H, 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): 783
(M ⁺ ) Example 5 5- [4- (6-t-butoxycarbonylmethoxy)-
2,5,7,8-Tetramethylchroman-2-ylmeth
Xy) benzyl] -2,4-dioxothiazolidine-3
-T-Butyl acetate In the separation step by column chromatography of 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 (9H, 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, dd, J = 10 and 14Hz), 3.56 (1H, dd, J = 4 and 14Hz),
3.87 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 ⁺ ) Example 6 5- [4- (6-hydroxy-2,5,7,8-tetra
Methyl-4-oxochroman-2-ylmethoxy) ben
Zil] -2,4-dioxothiazolidine-3-acetic acid t-
Butyl According to 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, heavy acetone): 1.46 (9H,
s), 1.50 (3H, s), 2.10 (3H, s), 2.22 (3H, s), 2.5-2.8 (1H, n
d), 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), 4.2
2 (2H, s), 4.82 (1H, dd, J = 4 and 10Hz), 6.96 (2H, d, J = 9H
z), 7.25 (2H, d, J = 9Hz).

Example 7 5- [4- (6-t-butoxycarbonylmethoxy-
2,5,7,8-tetramethyl-4-oxochroman-
Ilmethoxy) benzyl] -2,4-dioxothiazoli
Zin-3,5-di-t-butyl diacetate According to Example 4, 5- [4- (6-hydroxy-2,
5,7,8-Tetramethyl-4-oxochroman-2-
Ilmethoxy) benzyl] -thiazolidine-2,4-dione (1.5 g), anhydrous potassium carbonate (1.3 g), t-butyl bromoacetate (5.4 g) and acetone (10 ml) gave the target compound.

Rf value: 0.57 (developing solvent; cyclohexane: ethyl acetate = 7: 3) NMR spectrum (δ ppm, CDCl ₃ ): 1.42 (9H,
s), 1.46 (9H, s), 1.48 (3H, s), 1.52 (9H, s), 2.10 (3H, s), 2.2
6 (3H, s), 2.55-3.20 (4H, nd), 2.56 (3H, s), 3.23 (2H, s), 3.9
7 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 ⁺ ) Example 8 5- [4- (6-t-butoxycarbonylmethoxy-
2,5,7,8-tetramethyl-4-oxochroman-
2-ylmethoxy) benzyl] -2,4-dioxothia
Zolidine-3-tert-butyl acetate 5- [4- (6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy) benzyl] -obtained in Example 7. 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 (δ ppm, CDCl ₃ ): 1.47 (9H,
s), 1.50 (3H, s), 1.53 (9H, s), 2.10 (3H, s), 2.26 (3H, s), 2.5
6 (3H, 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 (2H,
s), 4.47 (1H, dd, J = 4 and 10Hz), 6.86 (2H, d, J = 9Hz), 7.1
6 (2H, d, J = 9Hz).

Mass spectrum (m / e): 683
(M ⁺ ) Example 9 3-Ethyl-5- [4- (6-hydroxy-2,5,
7,8-Tetramethylchroman-2-ylmethoxy) be
Nyl] thiazolidine-2,4-dione According to 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), 2.1
4 (3H, 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 (2H, d, J =
9Hz).

Example 10 5- [4- (6-hydroxy-4-hydroxyimino-
2,5,7,8-Tetramethylchroman-2-ylmeth
Xy) 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,
A mixture of 0.25 g pyridine and 5 ml methanol was left for 2 days at 25-30 ° 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 (δppm, heavy acetone): 1.42 (3H,
s), 1.45 (9H, s), 2.07 (3H, s), 2.17 (3H, s), 2.46 (3H, s), 3.0
3 (1H, 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 = 9Hz), 1
0.2 (1H, br.s, disappeared by adding heavy water).

Production Example 41 2- [4- (2,4-dioxothiazolidin-5-yl]
Methyl) phenoxymethyl] -4-hydroxyimino-
2,5,7,8-Tetramethylchroman-6-yloxy
2 -Methoxyethyl 2-acetate 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.
A mixture of 3 g, 0.3 g of pyridine and 6 ml of methanol was left at 25 to 30 ° C for 2 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 = 7: 3) to obtain the target compound.

Rf value: 0.32 (tailing) [developing solvent; benzene: ethyl acetate = 3: 2] NMR spectrum (δ ppm, heavy acetone): 1.43 (3H,
s), 2.06 (3H, s), 2.20 (3H, s), 2.46 (3H, s), 2.8-3.55 (2H, n
d), 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 = 4 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).

Example 11 5- [4- (6-t-butoxycarbonylmethoxy-4
-Hydroxyimino-2,5,7,8-tetramethyl chloride
Roman-2-ylmethoxy) benzyl] -2,4-dio
Xothiazolidine-3-t-butyl acetate 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, 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:
This was attached to 1) and 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), 2.4
7 (3H, 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.).

Example 12 5- [4- (6-t-butoxycarbonylmethoxy-4]
-Hydroxyimino-2,5,7,8-tetramethyl chloride
Roman-2-ylmethoxy) benzyl] -2,4-dio
Xothiazolidine-3,5-diacetic acid di-t-butyl 5- [4- (6-t-butoxycarbonylmethoxy-
2,5,7,8-tetramethyl-4-oxochroman-
2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3,5-diacetate di-t-butyl 350 mg,
Hydroxylamine hydrochloride 122 mg, pyridine 122 m
g and 4 ml of methanol at 25-30 ° C.
Left for 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 obtain the target compound.

Rf value: 0.48 (developing solvent; benzene:
Ethyl acetate = 10: 1) NMR spectrum (δppm, CDCl ₃ ): 1.45 (21
H, 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, b
rs), 4.11 (2H, s), 4.18 (2H, s), 6.83 (2H, d, J = 9Hz), 7.13 (2
H, d, J = 9Hz), 7.68 (1H, br.s).

Production Example 42 2- [4- (2,4-dioxothiazolidin-5-yl
Methyl) phenoxymethyl] -4-hydroxyimino-
2,5,7,8-Tetramethylchroman-6-yloxy
In accordance with ethyl acetate Preparation 41 2- [4- (5-2,4-dioxothiazolidin-ylmethyl) phenoxymethyl] -2,
5,7,8-Tetramethyl-4-oxochroman-6-
330 mg of ethyl oxyacetate, 170 mg of hydroxylamine hydrochloride, 170 mg of pyridine, 3 m of methanol
From l, a pale yellow powdery target compound was obtained.

Rf value: 0.67 (developing solvent; benzene:
Ethyl acetate = 1: 1) Mass spectrum (m / e): 556 (M ⁺ ) Production Example 43 2- [4- (2,4-dioxothiazolidin-5-yl)
Methyl) phenoxymethyl] -2,5,7,8-tetra
Methylchroman-6-yloxyacetic acid 2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl] -2,5,7,8-tetramethylchroman-6-yloxyacetic acid 2-methoxyethyl 220 mg A mixture of 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 (δ ppm, deuterated acetone): 1.38 (3H, s), 1.82-2.2 (2H, nd), 2.02 (3H, s), 2.15 (6)
H, s), 2.65 (2H, br.t, J = 7Hz), 3.08 (1H, dd, J = 9 and 14H
z), 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 = 9Hz), 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 the Production Example 30.

Melting point: 165-170 ° C. (white powder) Production Example 44 2- [4- (2,4-dioxothiazolidin-5-yl]
Methyl) phenoxymethyl] -2,5,7,8-tetra
Methyl-4-oxochroman-6-yloxyacetic acid Following the 2-methoxyethyl ester obtained in Preparation 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 (δ ppm, DMSO-
d ₆ ): 1.41 (3H, 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 14Hz), 4.01 (2H, s), 4.12 (2H, s), 4.61 (1H, dd, J = 4
And 9 Hz), 6.87 (2H, d, J = 9Hz), 7.15 (2H, d, J = 9Hz).

Sodium salt A sodium salt was obtained in the same manner as in Production Example 30.

Melting point: 160-165 ° C. (pale yellow powder) Production Example 45 2- [4- (2,4-dioxothiazolidin-5-yl]
Methyl) phenoxymethyl] -4-hydroxyimino-
2,5,7,8-Tetramethylchroman-6-yloxy
2- [4- (2,4-Dioxothiazolidin-5-ylmethyl) phenoxymethyl] acetate -4-hydroxyimino-
Ethyl 2,5,7,8-tetramethylchroman-6-yloxyacetate 8.9 mg, ethanol 1 ml and 0.
A mixture of 0.2 ml of 312M aqueous sodium hydroxide solution was allowed to stand at 0-5 ° C for 19 hours. After confirming the disappearance of the raw materials by HPLC, the reaction mixture was added with 0.35% hydrochloric acid 0.56
ml was added, and the solvent was distilled off 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, measured by fast atom bombardment method (FAB method) using glycerol as matrix): [M + H] ⁺ = 529 [M−H] ⁻ = 527, molecular weight MW = 528.

Sodium salt A sodium salt was obtained in the same manner as in Production Example 30.

Melting point: 173-180 ° C. (white powder) Example 13 5- [4- (6-hydroxy-2,5,7,8-tetra
Methylchroman-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 overnight at room temperature. 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 ⁺ ) Example 14 5- [4- (6-hydroxy-2,5,7,8-tetra
Methyl-4-oxochroman-2-ylmethoxy) ben
Diyl] -2,4-dioxothiazolidine-3-acetic acid According to Example 13, 5- [4- (6-hydroxy-
2,5,7,8-tetramethyl-4-oxochroman-
2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3-t-butyl acetate (350 mg) and a 4N hydrogen chloride dioxane solution (4 ml) gave a pale yellow powdery target product.

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

Mass spectrum (m / e): 513 (M ⁺ ) Example 15 5- [4- (6-hydroxy-4-hydroxyimino-)
2,5,7,8-Tetramethylchroman-2-ylmeth
Xy) benzyl] -2,4-dioxothiazolidine-3
-Acetic acid according to 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 4
A light brown powdery target product was obtained from 5 ml of an N hydrogen chloride dioxane solution.

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

Example 16 5- [4- (6-carboxymethoxy-2,5,7,8
-Tetramethylchroman-2-ylmethoxy) benz
] -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 g of -t-butyl acetate and 6 ml of 4N hydrogen chloride dioxane solution was left at room temperature overnight. After completion of the reaction, the treatment was carried out according to Example 13 to obtain the object product in the form of a pale yellow powder.

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

Mass spectrum (m / e): 557 (M ⁺ ) Example 17 5- [4- (6-Carboxymethoxy-2,5,7,8)
-Tetramethyl-4-oxochroman-2-ylmethoxy
Ci) Benzyl] -2,4-dioxothiazolidine-3-
According to acetic acid 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 target product in the form of a pale yellow powder 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 ⁺ ) Example 18 5- [4- (6-carboxymethoxy-4-hydroxy)
Imino-2,5,7,8-tetramethylchroman-2-
Ilmethoxy) benzyl] -2,4-dioxothiazoli
Zin-3-acetic acid According to Example 13, 5- [4- (6-t-butoxycarbonylmethoxy-4-hydroxyimino-2,5,
7,8-Tetramethylchroman-2-ylmethoxy) benzyl] -2,4-dioxothiazolidine-3-acetic acid t
-Butyl 370mg and 4N hydrogen chloride dioxane solution 4m
From l, a pale yellow powdery target product was obtained.

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

Example 19 5- [4- (6-carboxymethoxy- 2,5,7,8)
-Tetramethylchroman-2-ylmethoxy) benz
] -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 g of 3,5-diacetic acid di-t-butyl and 4 ml of 4N hydrogen chloride dioxane solution was left at room temperature overnight.
After completion of the reaction, the treatment was carried out according to Example 13 to obtain the object product in the form of a pale yellow powder.

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

Mass spectrum (m / e): 615 (M ⁺ ) Example 20 5- [4- (6-Carboxymethoxy-2,5,7,8)
-Tetramethyl-4-oxochroman-2-ylmethoxy
Si) benzyl] -2,4-dioxothiazolidine-3,
5-Diacetic acid According to 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
-Butyl 340mg and 4N hydrogen chloride dioxane solution 4m
The desired product in the form of a pale yellow powder was obtained from 1.

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

Mass spectrum (m / e): 629 (M ⁺ ) Example 21 5- [4- (6-carboxymethoxy-4-hydroxy)
Imino-2,5,7,8-tetramethylchroman-2-
Ilmethoxy) benzyl] -2,4-dioxothiazoli
Zin-3,5 -diacetic acidAccording to 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 powdery object. I got a thing.

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

Production Example 46 2- [4- (2,4-dioxothiazolidin-5-yl
Methyl) phenoxymethyl] -2,5,7,8-tetra
Methyl chroman- 6-yloxyacetate a) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (500 mg) and dimethylformamide (15 ml). 100% 55% oily sodium hydride was added thereto, and the mixture was stirred at room temperature for 1 hour.
Then, under ice cooling, 380 mg of ethyl bromoacetate was added dropwise,
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 resulting residue was subjected to preparative silica gel thin layer chromatography (developing solvent; benzene: ethyl acetate = 4: 1).
And the target compound was obtained.

Melting point: 104-106 ° C. Rf value of silica gel thin layer chromatography = 0.47
(Developing solvent; benzene: ethyl acetate = 4: 1) NMR spectrum (δ ppm, CDCl ₃ ): 1.32 (3H,
t, J = 7Hz), 1.40 (3H, s), 1.7-2.2 (2H, nd), 2.06 (3H, s), 2.14
(3H, 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 = 4 and 9Hz), 6.89 (2H, d, J = 9Hz), 7.16 (2
H, d, J = 9Hz), 7.8-8.8 (1H, br., Disappeared by adding heavy water).

B) 6-Ethoxycarbonylmethoxy-2,5,7,8-tetramethyl-2- (4-nitrophenoxymethyl) chroman produced according to Reference Example 40 was used as Reference Examples 41 and 43, and then Production Examples. According to 32, each was subjected to a catalytic reduction reaction, a diazotization reaction and a melbine arylation reaction, and then a thiazolidine ring formation reaction and a hydrolysis reaction, to obtain the title compound. Its melting point, Rf value by thin layer chromatography and NMR spectrum were in agreement with those in a).

Example 22 4- {5- [4- (6-hydroxy-2,5,7,8-
Tetramethylchroman-2-ylmethoxy) benzyl]
-2,4-Dioxothiazolidin-3-yl} butyric acid ethi
In accordance with 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 of silica gel thin layer chromatography
Value = 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
(3H, s), 2.63 (2H, br.t, J = 7Hz), 3.05 (1H, dd, J = 9 and 14H
z), 3.3-3.55 (1H, nd), 3.61 (2H, t, J = 7Hz), 3.85 and 3.9
7 (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), 6.86 ( 2
H, d, J = 9Hz), 7.13 (2H, d, J = 9Hz).

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

[0558]

[Chemical formula 61]

[0559]

[Table 122]

The esters shown in Table 15 were prepared in Production Example 4
Hydrolysis was performed according to 3, 45 or Example 13 to obtain the corresponding carboxylic acid derivative. They have the following physical properties.

[0561]

[Chemical formula 62]

[0562]

[Table 123]

[0563]

[Table 124]

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

Softening point: 57-63 ° C. NMR spectrum (δ ppm, 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 (1
H, dd, J = 4 and 8Hz), 6.91 (2H, d, J = 9Hz), 7.20 (2H, d, J = 9H
z).

Production Example 67 2- [4- (2,4-dioxothiazolidin-5-yl
Methyl) phenoxymethyl] -2,5,7,8-tetra
Methylchroman-6-yloxyacetamide According to Preparation Example 46a), 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4- Zeon 2
g, 55% 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
(3H, 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 = 8H
z), 7.16 (2H, d, J = 8Hz), 7.3-7.7 (2H, br.).

Production Example 68 5- [4- (2,5,7,8-tetramethyl-6-pipet
Lysinocarbonyl methoxychroman-2-ylmethoxy
Ci) Benzyl] thiazolidine-2,4-dione a) 2- [4- (2,4-dioxothiazolidine-5-
Ilmethyl) phenoxymethyl] -2,5,7,8-tetramethylchroman-6-yloxyacetate ethyl 0.5
A mixture of g and 2 ml 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: ethyl acetate = 3: 2) to obtain the target compound.

Softening point: 83-90 ° C. Rf value of silica gel 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 (3
H, s), 2.14 (3H, s), 2.64 (2H, br.t, J = 7Hz), 3.08 (1H, dd, J = 9
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 (2H,
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,
85 mg of piperidine, 243 mg of triethylamine, 307 mg of 2-chloro-1-methylpyridinium iodide,
A mixture of and 7 ml of dioxane was warmed 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. This compound was obtained by analyzing the compound obtained in a), Rf value by silica gel thin layer chromatography, mass spectrum, and NM.
The R spectrum data were in agreement.

Production Example 69 5- [4- (6-morpholinocarbonylmethoxy-2,-
5,7,8-Tetramethylchroman-2-ylmethoxy
Ci) Benzyl] thiazolidine-2,4-dione According to Preparation Example 68b), 2- [4- (2,4-dioxothiazolidin-5-ylmethyl) phenoxymethyl]
The target compound produced 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 of silica gel thin layer chromatography
Value = 0.41 (developing solvent; benzene: ethyl acetate = 2:
3) NMR spectrum (δ ppm, deuterated acetone): 1.40 (3H,
s), 1.75-2.2 (2H, nd), 2.03 (3H, s), 2.14 (6H, s), 2.65 (2H, b
rt, 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), 4.7
3 (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-trimethylchloro
Mann-2-carboxylate ethyl 6-hydroxy-5,7,8-trimethylchromone-2-carboxylate 14 g was dissolved in 320 ml of acetic acid, and in the presence of 3.5 g of 10% palladium carbon, hydrogen pressure was 3 atm, and pressure was 60 to 65. Catalytic reduction was carried out at ℃ 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 target product was 108 to 109 ° C.

NMR spectrum (δppm, CDC
l ₃ ): 1.28 (3H, t, J = 7Hz), 2.07 (3H, s), 2.17 (6H, s), 1.9
-2.3 (2H, nd), 2.65 (2H, 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-trimethyi
Lucroman-2-carboxylate ethyl 6-hydroxy-5,7,8-trimethylchromane-2-carboxylate 14.3 g and a mixture of 130 ml of dimethylformamide were added to a mixture of 5-10 under a nitrogen stream.
At 0 ° C. 3 g 55% oily sodium hydride (wash twice with cyclohexane) are added in portions. After stirring at room temperature for 1 hour, the mixture was ice-cooled to 3 to 5 ° C, and 5.6 g of chloromethyl methyl ether was added dropwise. After the dropping, stir for 1 hour at room temperature. The reaction mixture is poured into ice water and extracted with cyclohexane. 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 = 2).
5: 1) to obtain the target compound.

Rf of silica gel thin layer chromatography
Value = 0.41 (developing solvent; benzene: ethyl acetate = 2)
0: 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
(3H, 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-trimethyi
Le-2-octyl chroman-2-carboxylate diisopropylamine 2 g and tetrahydrofuran 80 m
l-mixture under a nitrogen stream at -60 to -50 ° C and n-
7.8 ml of a hexane solution of butyl lithium (n-butyl lithium 1.62 mmol / ml) was added dropwise, and the mixture was allowed to stand at room temperature for 10 minutes. Then, at -60 ° C, ethyl 6-methoxymethoxy-5,7,8-trimethylchroman-2-
About 4 ml of carboxylate and about 10 ml of tetrahydrofuran
It was added to the mixture and stirred for 1 hour. Then octyl bromide 5
g was dissolved in about 20 ml of tetrahydrofuran and added -6
Stir at 0 ° C for 1 hour, at room temperature for 1 hour, then at 50 ° C for 1
Heated for hours. 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 of silica gel thin layer chromatography
Value = 0.58 (developing solvent; benzene: ethyl acetate = 2)
0: 1) NMR spectrum (δppm, 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 (3H, 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 aluminum hydride (0.45 g) and tetrahydrofuran (30 ml) were added to a mixture of ethyl under a nitrogen stream.
6-methoxymethoxy-5,7,8-trimethyl-2-
3.3 g of octyl chroman-2-carboxylate,
The solution 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, CDC
l 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-octyl chroma
Down 6-methoxy-methoxy -5,7,8- trimethyl-2-
To a mixture of 3 g of octyl chroman-2-ylmethanol and 25 ml of dimethylformamide, 0.38 g of 55% oily sodium hydride was added at room temperature under a nitrogen stream, and then heated at 50 ° C. for 2 hours. After adding a mixture of 1.4 g of p-chloronitrobenzene and 2 ml of benzene under ice cooling, 5
Heated at 0 ° 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 evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: benzene) to obtain the target compound.

Rf of silica gel thin layer chromatography
Value = 0.46 (developing solvent; benzene) NMR spectrum (δ ppm, 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 (3H, s), 2.19 (3H, s), 2.6 (2H, br.t, J = 7Hz), 3.60 (3H, s),
4.05 (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 1
A mixture of 0.75 ml of 0% sulfuric acid was heated under reflux 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 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 (δ ppm, CDC
l 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 adding heavy water), 6.97 (2H, d, J = 9H
z), 8.19 (2H, d, J = 9Hz).

Reference Example 7 (A-3-Acylation) 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. The reaction mixture was poured into water and extracted with benzene. The extract was washed with 5% 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 (δ ppm, CDC
l ₃ ): 0.75-1.0 (3H, m), 1.1-1.65 (12H, m), 1.65-2.15 (4
H, nd), 1.99 (3H, s), 2.04 (3H, s), 2.08 (3H, s), 2.32 (3H, s),
2.63 (2H, br.t, J = 7Hz), 4.07 (2H, s), 6.98 (2H, d, J = 9Hz), 8.
20 (2H, d, J = 9Hz).

Reference Example 8 (A-3-H ₂ ) 6-acetoxy-2- (4-aminophenoxymethyl)
-5,7,8-Trimethyl-2 -octylchroman 6-acetoxy-5,7,8-trimethyl-2- (4-
Nitrophenoxymethyl) -2-octylchroman 4
g, 10% palladium on carbon 0.8 g, methanol 30 m
A mixture of 1 and 10 ml of benzene was shaken for 5 hours at a hydrogen pressure of 3-5 atm using a Parr hydrogenation device. 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
(3H, 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
= 7Hz), 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-to]
Limethyl-2-octylchroman-2-ylmethoxy)
Phenyl] -2-chloropropionate 6-acetoxy-2- (4-aminophenoxymethyl)
-5,7,8-Trimethyl-2-octylchroman 3.
5 g of a mixture of 2 g and 35 ml of acetone under a nitrogen stream.
Concentrated hydrochloric acid 3.5 ml at 10 ° 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, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: cyclohexane:
Ethyl acetate = 10: 1) was added to obtain the target compound.

Rf of silica gel thin layer chromatography
Value = 0.27 (developing solvent; cyclohexane: ethyl acetate = 9: 1) NMR spectrum (δ ppm, CDCl ₃ ): 0.8-1.05
(3H, 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 =
7Hz), 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 = 7H
z), 6.85 (2H, d, J = 9Hz), 7.13 (2H, d, J = 9Hz).

Reference Example 10 (D-1) 6-acetoxy-2-methyl-2- (4-nitropheno)
Xymethyl) -4-oxo-7- (1,1,3,3-thel
Tramethylbutyl ) chroman 5-acetoxy-2-hydroxy-4- (1,1,3,3
3-tetramethylbutyl) acetophenone 23 g, 1-
(4-Nitrophenoxy) -2-propanone 14.7
g, pyrrolidine 8 g, and a mixture of benzene 300 ml,
Stir for 3 hours at room temperature. 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 is poured into ice water and extracted with benzene,
The extract was washed with 5% hydrochloric acid and then 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 = 20: 1) and recrystallized from methanol to obtain the target compound.

Melting point: 165.5-167 ° C. NMR spectrum (δ ppm, CDCl ₃ ): 0.76 (9H,
s), 1.36 (6H, s), 1.57 (3H, s), 1.83 (2H, s), 2.32 (3H, s), 2.7
4 (1H, d, J = 17Hz), 3.10 (1H, d, J = 17Hz), 4.11 and 4.24 (2
H, 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-then
Tramethylbutyl) chroman 6-acetoxy-2-methyl-2- (4-nitrophenoxymethyl) -4-oxo-7- (1,1,3,3-tetramethylbutyl) chroman 12.3 g, methanol 200 ml And dissolved in a mixture of 20 ml of benzene,
Reduction was carried out at room temperature for 6 hours under a hydrogen pressure of about 1 atm in the presence of 2.4 g of 10% palladium carbon. 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 of silica gel thin layer chromatography
Value = 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), 2.6
6 (1H, d, J = 17Hz), 3.10 (1H, d, J = 17Hz), 3.4 (2H, br.s, disappeared by addition of 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-tetramethylbutyrate
Ru) chroman-2-ylmethoxy] phenyl] -2-ku
According to loropropionate Reference Example 9, 6-acetoxy-2- (4-aminophenoxymethyl) -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 1
The target product produced from 00 ml and about 8 ml of water has the following physical properties.

Rf of silica gel thin layer chromatography
Value = 0.32 (developing solvent; benzene: ethyl acetate = 2)
0: 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 (2H, 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
dissolved in a mixed solvent of 10 ml of benzene and 10 ml of benzene, and under ice cooling,
Sodium borohydride (1 g) was added, and the mixture was stirred with ice for 30 minutes. 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 of silica gel thin layer chromatography
Value = 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, n
d), 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 = 9H
z), 7.08 (1H, s), 8.18 (2H, d, J = 9Hz).

Reference Example 14 (F-3) 6-Hydroxy-2-methyl-2- (4-nitropheno)
Xymethyl) -7- (1,1,3,3-tetramethylbutane
Chill) -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 evaporated under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: benzene), and R in silica gel thin layer chromatography (developing solvent; benzene: ethyl acetate = 20: 1).
Target compound (1) with f value = 0.53 and Rf value = 0.5
0 target compound (2) was obtained.

NMR spectrum of (1) (δ ppm, C
_{DCl 3): 0.75 (9H,} s), 1.38 (6H, s), 1.56 (3H, s), 1.89
(2H, s), 4.09 (2H, s), 4.43 (1H, s, disappeared by adding heavy water), 5.63
(1H, d, J = 10Hz), 6.32 (1H, s), 6.41 (1H, d, J = 10Hz), 6.73 (1
H, s), 6.96 (2H, d, J = 9Hz), 8.20 (2H, d, J = 9Hz).

NMR spectrum of (2) (δ ppm, C
_{DCl 3): 0.76 (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), 6.4
3 (1H, d, J = 10Hz), 6.69 (1H, s), 6.79 (1H, s), 6.93 (2H, d, J = 9
Hz), 8.18 (2H, d, J = 9Hz).

Reference Example 15 (F-5) 6-acetoxy-2- (4-aminophenoxymethyl)
-2-methyl-7- (1,1,3,3-tetramethylbutane
Chill) chroman 6-acetoxy-2-methyl-2- (4-nitrophenoxymethyl) -7- (1,1,3,3-tetramethylbutyl) -2H-chromene 9.1 g, 10% palladium on carbon 2 g, A mixture of 150 ml of methanol was shaken using a Parr hydrogenation device at a hydrogen pressure of 3 to 5 atmospheres for 10 hours. 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 of silica gel thin layer chromatography
Value = 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-chloropropione
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 1
The target product prepared from 8 g, 260 mg of cuprous oxide, 90 ml of acetone and about 5 ml of water has the following physical properties.

Rf of silica gel thin layer chromatography
Value = 0.55 (developing solvent; benzene: ethyl acetate = 2)
0: 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
(2H, 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), 4.37
(1H, t, J = 7Hz), 6.72 (1H, s), 6.85 (1H, s), 6.86 (2H, d, J = 9H
z), 7.16 (2H, d, J = 9Hz).

Reference Example 17 (E-1) Ethyl 6-hydroxy-5,7,8-trimethyl-4
12 g of -oxochroman-2-carboxylate ethyl 6-hydroxy-5,7,8-trimethylchromone-2-carboxylate was dissolved in 250 ml of dimethylformamide, and 16 g of 10% palladium carbon was added.
In the presence of hydrogen peroxide at 50 at 60 ° C. for 5 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 (δ ppm, CDCl ₃ ): 1.26 (3H,
t, J = 7Hz), 2.23 (6H, s), 2.52 (3H, s), 2.98 (2H, d, J = 7Hz), 4.
24 (2H, q, J = 7Hz), 4.83 (1H, s), 4.94 (1H, t, J = 7Hz).

The above target compound was filtered off, the filtrate was extracted with ethyl acetate, the extract was 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)
The target compound was obtained from the first fraction and ethyl 4,6-dihydroxy-5,7,
8-Trimethylchroman-2-carboxylate was obtained.

Melting point: 138-144 ° C. Reference Example 18 (E-2) ethyl spiro [6-hydroxy-5,7,8-trimethyl]
Chilchroman-4,2 '-[1,3] dithian] -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 a 00 ml solution under ice cooling, and the mixture was allowed to stand at room temperature for 24
Left for 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.

Melting point: 186-188 ° C. NMR spectrum (δ ppm, 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 1% of 55% sodium hydride was sonicated at room temperature for 1 hour, 3 g of chloromethyl methyl ether 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 of silica gel thin layer chromatography
Value = 0.21 (developing solvent; hexane: ethyl acetate = 5:
1) NMR spectrum (δ ppm, 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-trimethylchroma
-4,2 '-[1,3] dithiane] -2-carboxy
In a 30 ml tetrahydrofuran solution of 2.9 g of diisopropylamine under a nitrogen atmosphere at a rate of −60 ° C. to −50 ° C.,
17.7 ml of a hexane solution of n-butyllithium (n-butyllithium 1.62 mmol / ml) was added dropwise,
It was left at room temperature for 10 minutes. Then, 6 g of ethyl spiro [6-methoxymethoxy-5,7,8-trimethylchroman-4,2 '-[1,3] dithiane] -2-carboxylate was dissolved in 10 ml of tetrahydrofuran and added dropwise at -60 ° C. 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, the mixture was stirred at room temperature for 1 hour and at 45 to 50 ° C. for 1.5 hours, and further 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 evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 10: 1) to obtain the target compound (pale yellow oil).

Rf of silica gel thin layer chromatography
Value = 0.57 (developing solvent; benzene: ethyl acetate = 2)
0: 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), 2.8
3 (3H, s), 2.97-3.5 (2H, m), 3.59 (3H, s), 3.73 (1H, d, J = 14H
z), 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-meth]
Xymethoxy-5,7,8-trimethylchroman-4,
2 '-[1,3] Dithian] -2-ylmethanolethyl 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, and the solvent was distilled off under reduced pressure, followed by silica gel thin layer chromatography (developing solvent; benzene: ethyl acetate = 2).
The target compound was obtained in the form of a pale yellow oil with Rf value = 0.36 in 0: 1).

NMR spectrum (δ ppm, CDC
l ₃ ): 0.87 (9H, d, J = 7Hz), 1.0-2.0 (12H, m), 2.0-2.5 (2
H, 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), 3.6
1 (3H, s), 3.76 (1H, dd, J = 6 and 12Hz), 4.89 (2H, s).

Reference Example 22 (E-6) Spiro [2- (3,7-dimethyloctyl) -6-meth]
Xymethoxy-5,7,8-trimethyl-2- (4-di
Trophenoxymethyl) 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, in a nitrogen stream, at room temperature, 55% oily sodium hydride 0.46 g
Was added and then heated at 50 ° C. for 2 hours. P- under ice cooling
A mixture of 1.66 g of chloronitrobenzene and 3 ml of benzene was added dropwise and then 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, and the residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 50: 1) to obtain the target compound.

Rf of silica gel thin layer chromatography
Value = 0.55 (developing solvent; benzene: ethyl acetate = 2)
0: 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
(1H, 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-nitrophenoxy
Methyl) -4-Okisokuroman spiro [2- (3,7-dimethyl-octyl) -6-methoxymethoxy -5,7,8- trimethyl-2- (4-nitrophenoxy-methyl) 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 heated under reflux 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 distilled off under reduced pressure,
The residue is subjected to silica gel column chromatography (eluent;
The mixture was subjected to benzene: ethyl acetate = 100: 3), and the obtained crystals were recrystallized from a mixed solution of benzene and hexane to obtain the target compound.

Melting point: 121-123 ° C. NMR spectrum (δ ppm, CDCl ₃ ): 0.85 (9H,
d, J = 7Hz), 1.0-1.7 (10H, m), 1.7-2.1 (2H, m), 2.11 (3H, s),
2.21 (3H, s), 2.55 (3H, s), 2.76 and 2.98 (2H, AB type, J = 16
Hz), 4.16 (2H, s), 4.57 (1H, s, disappears 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-nitrophenoxy
Methyl) -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 of silica gel thin layer chromatography
Value = 0.41 (developing solvent; benzene: ethyl acetate = 2)
0: 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
(3H, 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-to
Limethyl-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 of silica gel thin layer chromatography
Value = 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
(3H, s), 2.41 (3H, s), 2.77 and 3.00 (2H, AB type, J = 16Hz),
3.4 (2H, br.s, disappeared by addition of 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-o
Xoxochroman-2-ylmethoxy] phenyl] -2-ku
Lolo according to propionate Reference Example 9, 6- acetoxy-2- (4-aminophenoxy) -2- (3,7-dimethyl octyl) -5,7,8- trimethyl-4- Okisokuroman 1.6g , Sodium nitrite 0.28g, concentrated hydrochloric acid 1.7
ml, ethyl acrylate 3.3 ml, cuprous oxide 0.1
The target compound produced from g has the following physical properties.

Rf of silica gel thin layer chromatography
Value = 0.45 (developing solvent; benzene: ethyl acetate = 2)
0: 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 2.9
8 (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 = 7Hz),
4.37 (1H, t, J = 7Hz), 6.83 (2H, d, J = 9Hz), 7.15 (2H, d, J = 9H
z).

Reference Example 27 (D-1) 6-acetoxy-7-t-butyl-2-methyl-2-
(2-Methyl-5-nitrophenoxymethyl) -4-o
According to Xochroman Reference Example 10, 5-acetoxy-4-t-butyl-2-hydroxyacetophenone 4.78 g, 1- (2
The pale red foamy target product 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 = 1
6.5Hz), 3.15 (1H, d, J = 16.5Hz), 4.43 (2H, AB type, J = 12Hz), 6.
97 (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-methylpheno)
Xymethyl) -7-t-butyl-2-methyl-4-oxy
According to Sochroman Reference Example 11, 6-acetoxy-7-t-butyl-2-methyl-2- (2-methyl-5-nitrophenoxymethyl) -4-oxochroman 7.3g, 10% palladium on carbon 1g and ethanol Hydrogenation was performed using 100 ml to obtain the target compound in the form of a pale red foam.

Rf value by silica gel thin layer chromatography = 0.13 (developing solvent; benzene: ethyl acetate =
5: 1) NMR spectrum (δ ppm, deuterated acetone): 1.33 (9H,
s), 1.56 (3H, s), 1.95 (3H, s), 2.31 (3H, s), 2.80 (1H, d, J = 1
6.5Hz), 3.10 (1H, d, J = 16.5Hz), 4.06 (2H, s), 3.90-4.70 (2
H, br., Disappeared by adding heavy water), 6.18 (1H, dd, J = 8 and 1.5Hz),
6.28 (1H, d, J = 1.5Hz), 6.78 (1H, d, J = 8Hz), 7.00 (1H, s), 7.4
7 (1H, s).

Reference Example 29 (D-3) Ethyl 3- [3- (6-acetoxy-7-t-butyl)
-2-methyl-4-oxochroman-2-ylmethoxy
Ci) -4-Methylphenyl] -2-chloropropione
According to Reference Example 12, 6-acetoxy-2- (5-amino-2-methylphenoxymethyl) -7-t-butyl-
2-methyl-4-oxochroman 5.53 g, sodium nitrite 1.2 g, concentrated hydrochloric acid 2.4 ml, ethyl acrylate 14 ml, cuprous oxide 190 mg, and acetone 5
The pale yellow oily target compound produced from 0 ml has the following physical properties.

Rf value by silica gel thin layer chromatography = 0.41 (developing solvent; benzene: ethyl acetate =
10: 1) NMR spectrum (δppm, CDCl ₃ ): 1.22 (3H,
t, J = 7.5Hz), 1.32 (9H, s), 1.57 (3H, s), 2.10 (3H, s), 2.30 (3
H, 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 (2
H, AB type, J = 10Hz), 4.18 (2H, q, J = 7.5Hz), 4.40 (1H, t, J = 7H
z), 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 dimethylformamide (20 ml) were mixed in a stream of nitrogen at room temperature with 55% oily sodium hydride (0.96 g, cyclohexane). Wash 4 times with 4). 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.

R for silica gel column chromatography
f value = 0.56 (developing solvent; benzene: ethyl acetate = 1)
0: 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) chroma
Down 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
% Sulfuric acid aqueous solution (1 g) and the mixture is heated at 55 to 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 of silica gel thin layer chromatography
Value = 0.46 (developing solvent; benzene: ethyl acetate = 1)
0: 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),
2.67 (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-Acylation) 6-acetoxy-2,5,7,8-tetramethyl-2-
(5-Nitropyridin-2-yloxymethyl) chroma
In accordance with Reference Example 7, 6-hydroxy-2,5,7,8-
The target substance 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 of silica gel thin layer chromatography
Value = 0.52 (developing solvent; benzene: ethyl acetate = 1)
0: 1) NMR spectrum (δ ppm, 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.
36 (1H, dd, J = 9 and 3Hz), 9.07 (1H, d, J = 3Hz).

Reference Example 33 (A-3-H ₂ ) 6-acetoxy-2- (5-aminopyridin-2-yl)
Oxymethyl) -2,5,7,8-tetramethylchroma
Down 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, and reduced at room temperature for about 20 hours at a hydrogen pressure of about 1 atm in the presence of 1.5 g of 10% palladium carbon. .
The palladium carbon was filtered off, and the obtained filtrate was concentrated under reduced pressure to obtain the desired product.

Rf of silica gel thin layer chromatography
Value = 0.04 (developing solvent; benzene: ethyl acetate = 1)
0: 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),
2.30 (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) pyridine
-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.
1 g, concentrated hydrochloric acid 5 ml, ethyl acrylate 10 g, cuprous oxide 175 mg, acetone 40 ml and water about 2.5 g
The target product produced from has the following physical properties.

Rf of silica gel thin layer chromatography
Value = 0.45 (developing solvent; benzene: ethyl acetate = 1)
0: 1) NMR spectrum (δppm, CDCl ₃ ): 1.26 (3H,
t, J = 7.5Hz), 1.40 (3H, s), 1.7-2.3 (2H, m), 1.99 (3H, s), 2.0
2 (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)
-Tetramethylchroman-2-ylmethoxy) phenyl
2-]-2-Chloro-2-methylpropionate According to Reference Example 9, 6-acetoxy-2- (4-aminophenoxymethyl) -2,5,7,8-tetramethylchroman 2 g, acetone 25 ml, 35% hydrochloric acid 3 ml, sodium nitrite 0.7 g, water 1 ml, ethyl methacrylate 8
The target product produced from 0.2 g of cuprous oxide and 0.2 g of cuprous oxide has the following physical properties.

Rf of silica gel thin layer chromatography
Value = 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 (2H,
d, J = 9Hz), 7.14 (2H, d, J = 9Hz).

Reference Example 36 (H-1) 6-acetoxy-2-hydroxy-5,7,8-trimethyl
Cyl-2- (4-nitrophenoxymethyl) -4-oxy
Sochroman 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.

Melting point: 204-207 ° C. NMR spectrum (δ ppm, DMSO-d ₆ ): 2.05
(3H, s), 2.11 (3H, s), 2.34 (6H, s), 2.76 (1H, d, J = 17Hz), 3.2
4 (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 (2
H, d, J = 9 Hz).

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

Rf of silica gel thin layer chromatography
Value = 0.48 (developing solvent; ethyl acetate) NMR spectrum (δ ppm, CDCl ₃ ): 2.08 (3H,
s), 2.10 (3H, s), 2.32 (3H, s), 2.41 (3H, s), 2.78 and 3.03
(2H, AB type, J = 16Hz), 3.4-4.3 (3H, br.s, disappears by adding heavy water), 3.98 and 4.12 (2H, AB type, J = 10Hz), 6.62 (2H, d, J = 9H)
z), 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 g have the following physical properties.

Rf of silica gel thin layer chromatography
Value = 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
(4H, 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 5.6 g of sodium hydroxide, 150 ml of ethyl alcohol and 20 ml of water were added.
The mixed solution of ml 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).
The target compound was obtained.

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 (12
H, s), 2.07 (3H, s), 2.27 (3H, s), 2.57 (3H, s), 2.68 (1H, d, J =
16.5Hz), 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
To 100 ml of F was added 1.6 g of 55% oily sodium hydride 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 stirred at room temperature 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 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, 3H,
t, J = 7Hz), 1.43 (3H, s), 1.7-2.1 (2H, nd), 2.06 (3H, s), 2.14
(3H, 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 = 9
Hz), 8.17 (2H, d, J = 9Hz).

Reference Example 41 2- (4-aminophenoxymethyl) -6-t-butoxy
Cycarbonylmethoxy-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 carbon, 150 ml of methanol, and 50 ml of dimethylformamide was shaken for 7 hours under a hydrogen pressure of 3 to 5 atm using a Parr hydrogenation device. 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, n
d), 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
(2H, 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 (δ ppm, CDCl ₃ ): 1.38 (3H,
t, J = 7Hz), 1.40 (3H, s), 1.7-2.1 (2H, nd), 2.08 (3H, s), 2.12
(3H, 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 3.91 (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-chloropropion
Ethyl acid 2- (4-aminophenoxymethyl) -6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman A mixture of 16 g and 160 ml of acetone was placed in a nitrogen stream at 5 to 10 ° C. Then, 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 sequentially added dropwise. Inner temperature 40 ~
The temperature was set to 43 ° C., and 0.5 g of cuprous oxide was gradually added. About 3
Generation of nitrogen is completed in 0 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 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 (3
H, 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
4.09 (2H, AB type, J = 10Hz), 4.05-4.35 (2H, nd), 4.18 (2H, s),
4.37 (1H, t, J = 7Hz), 6.85 (2H, d, J = 8Hz), 7.14 (2H, d, J = 8Hz)
.

Reference Example 44 2-chloro-3- [4- (6-ethoxy-2,5,7,
8-Tetramethylchroman-2-ylmethoxy) phenyl
Ethyl] 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 The target compound was obtained from 26.8 g of ethyl acrylate, 0.4 g of cuprous oxide, and 100 ml of acetone.

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).

[0663]

INDUSTRIAL APPLICABILITY The thiazolidine derivative of the present invention has a blood lipid metabolism improving action, a blood glucose metabolism improving action and an aldose reductase inhibiting action, and is useful for hyperlipidemia, diabetes, diabetic complications and the like.

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location C07D 417/14 213 // (C07D 417/12 277: 00 311: 00) (C07D 417/14 213: 00 277 (00) 311: 00) (72) Inventor Mt. Fujita 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Tsutomu Kanai 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock company (72) Inventor Mitsuo Yamazaki 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock Company (72) In-house Kazuo Hasegawa 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. In-company (72) Inventor Hokoshi Ono Sankyo Co., Ltd. 1-25-2 Hiromachi, Shinagawa-ku, Tokyo

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. R ³ and R ³ ′ described below 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 an alkyl group which may have a substituent, 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 a methylene group, a carbonyl group, a formula> CH-OR ³ ′ Group (in the formula, R ³ ′ has the same meaning as described above), 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 may form a double bond with U described later, where U is a single bond or a methylene group. Is shown or forms a double bond with W, W is a carbonyl group, a formula> = N-OV group or a formula> = N-OR ³ '
_{When it represents a} group (in the formula, V and R ³ ′ _a have the same meanings as described above), it may form a double bond with R ¹ , and n represents an integer of 1 to 10, and Y May represent an oxygen atom or an imino group, Z may represent an oxygen atom or an imino group, or may represent a sulfur atom when W is a methylene group. ] The thiazolidine derivative or its salt represented by these.