JPS625981A - Production of thiazolidine derivative - Google Patents

Abstract

PURPOSE:To obtain the objective compound by using an acetophenone derivative and a nitro compound as raw materials, reducing and diazotizing the nitro group, subjecting the product to Meerwein arylation with an acrylic acid derivative and reacting with thiourea. CONSTITUTION:The objective compound of formula VII (Y and Z are O or imino) can be produced by (1) reacting the compound of formula I (R<2> is H, lower alkyl, etc.; R<3> is H, aliphatic lower acyl, etc.; R<4> and R<5> are H, lower alkyl, etc.) with the compound of formula II (R<1> is H, lower alkyl, etc.; n is 1-3), reducing and optionally acylating the resultant compound of formula III, converting the compound to the compound of formula IV by elimination reaction, reducing and diazotizing the product, subjecting to the Meerwein acylation reaction with the acrylic acid derivative of formula V (A' is CN, etc.), reacting the produced compound of formula VI (X is halogen; A is A', etc.) with thiourea and, if necessary, hydrolyzing the reaction product.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has an effect of improving blood lipid and glucose metabolism, that is, an effect of lowering blood peroxide lipids, a blood triglyceride lowering effect, a blood cholesterol lowering effect, and a blood sugar lowering effect,
The present invention also relates to a method for producing a novel thiazolidine derivative with extremely low toxicity. More specifically, the present invention is based on the general formula [Formula (1), R1 and R2 are the same or different and represent a hydrogen atom or a lower alkyl group, R3 and R
5' is a hydrogen atom, an aliphatic lower acyl group, an alicyclic acyl group, an optionally substituted aromatic acyl group, a heterocyclic acyl group, an optionally substituted aromatic aliphatic acyl group group, lower a, and 几5 are the same or different and represent a hydrogen atom, a lower alkyl group, or a lower alkoxy group, and n is 1 to 3.
W is a methylene group, a carbonyl group, or a formula>-
OR'', Y and Z represent an oxygen atom or an imino group], and relates to a method for converting thia to a methylene group.

Constitution of the Invention The thiazolidine derivative according to the present invention can be produced as follows.

Method A Method A has already been proposed by the present inventors in a patent application filed in 1982-158.
This method is detailed in No. 375 (abbreviated as No. 1), and is advantageously used to produce a compound of general formula (1) in which W is a methylene group. By Kenpo, as shown below, compound (3) is converted into target compound (1) (W:〉c
I am guided by (2). (A-1 → A-5) In the above formula, ul, R2, R3, R4, R5 and n have the same meanings as described above, m is an integer from 0 to 2,
X is a halogen atom, A is a cyano group, carboxy group, alkoxycarbonyl group, carbamoyl group or formula -00
0M (in the formula, M represents an equivalent cation), (
! ! (W:)0142) represents a thiazolidine derivative in which W is a methylene group, and B 10 will be shown later.

This step is a reduction step using a metal hydride such as lithium aluminum hydride or bitride (sodium bis(2-methoxyethoxy)aluminum hydride).

This step is a step that leads to a chroman alcohol (5) having a chroman alcohol +41 onitro groups.

It is preferable to protect the phenolic hydroxyl group prior to the reaction, and the hydroxyl protecting group R10 is preferably an alkoxyalkyl group such as methoxymethyl or 2-tetrahydropyranyl. Chroman alcohols having a protected phenolic hydroxyl group can be isolated, but have the same meaning as "without isolation." ) to lead to chromans (5) having a nitro group.

A-3 This step is a step of reducing the nitro compound (5) obtained in A-2 to the corresponding amine compound (6).

In the reduction reaction, the protecting group BIG for the phenolic hydroxyl group of the nitro compound (5) may be left as is, or may be deprotected, or may be further converted into another group, such as an acyl group such as an acetyl group or a benzoyl group. It is preferable to change it to an acyl group. When deprotecting compound (5), the deprotection step is achieved by hydrolyzing (5) in the presence of a low concentration of acid.

When converting compound (5) into a protecting group such as a silyl group, the acylation is performed by further converting the deprotected compound by the above hydrolysis into an acid halide such as acetyl chloride or benzoyl chloride, or an acid anhydride such as acetic anhydride. This is achieved by treatment with an acylating agent as shown in the following.

The reduction reaction from the nitro compound (5) to the amine compound (6) is catalytic reduction or reduction with metals such as zinc and iron and acids (for example, mineral acids such as hydrochloric acid and sulfuric acid, or organic acids such as acetic acid). However, catalytic reduction is preferred.

In this step, the aromatic amino compound (6) is diazotized to obtain an acrylic acid derivative represented by the general formula OH, 2:0H-A' (where A' is a cyan group, a carboxy group, an alkoxycarbonyl group, or a carbamoyl group). ) is converted into α-logenocarboxylic acid derivatives (7), which are the precursors of the object compound (1) of the present invention, by subjecting it to a mailpine arylization reaction.

Human-5 In this step, compound (7) is reacted with thiourea to produce a thiazolidine derivative in which Z is an imino compound [fll
.
. )I2)], and furthermore, R3,゛
is a hydrogen atom [Q2 (W:
0H2)].

Method B Method B uses the general formula (11, W is a methylene group, n
2. Among the chroman alcohols (4), those in which n is 2, (8), for example, can be prepared by the method described in Journal of the American Oil Chemistry Society, Vol. 51, p. 200 (1974). )↓A-5 (1) (W:>CH2) As mentioned above, it can be produced in multiple steps, but it can be produced in one step according to the method shown in JP-A No. 58-201775. A-2 to A-
The desired compound can be produced in 5 steps. R1
, B2°R5, R4, and R5 have the same meanings as described above.

Method C Method C is also advantageously used to produce the target compound in general formula (1) in which W is a methylene group.

This method is based on the method described in Journal of Medicinal Chemistry, Vol. 18, p. 934 (1975), and FL1'(R1' excludes the hydrogen atom from the above definition of B1) is placed at the 2-position of the chroman ring. ) can be advantageously used to introduce

By this method, as shown below, compound (9) is led to target compound (1) (w:':10H2).

(C-1→O-11) In the above formula, B1', R2, R4, B5. and Hlo have the same meanings as described above, and B represents a protecting group for carboxylic acid, such as an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group, or a phenyl group which may be substituted, but is preferred. represents a lower alkyl group, and may represent a leaf atom if no protection is required.

Each step is essentially equivalent to the method described in the above-mentioned document.

The 0-5 step is a step of protecting the phenolic hydroxyl group, which is performed as necessary, but it is preferable to protect the phenolic hydroxyl group prior to the C-6 step. In the case of protecting a hydroxyl group, the protecting group R10 may be a general protecting group for a phenolic hydroxyl group, such as an alkoxyalkyl group such as methoxymethyl or 2-tetrahydropyranyl, or a substituted benzyl group; Examples include acyl groups such as acetyl and benzoyl, but alkoxyalkyl groups are preferred. Reactions to introduce protecting groups are usually carried out using alkali or alkaline earth metal hydrides, such as sodium hydride, potassium hydride, calcium hydride, or sodium methoxide, sodium ethoxide, potassium tert-butoxide. This is accomplished by using an alkoxy alkylating agent such as chloromethyl methyl ether, or alternatively an alkylating agent such as benzyl halide, in the presence of a base such as an alkali metal alcoholade. In this reaction, examples of solvents include ethers such as diethyl ether, tetrahydrofuran, and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, hexane,
Examples include aliphatic hydrocarbons such as heptane, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, and sulfones such as sulfolane. The ratio of the compound O2 to the alkylating agent is not particularly limited, but it is advantageous to use the alkylating agent in a slight to excess amount relative to α2.

Preferably compound g! The alkylating agent is present in an amount of 1 to 10 mol per mol. Although reaction conditions such as reaction temperature and reaction time vary depending on the raw materials and solvent used, the reaction is usually carried out at 0 to 50°C, preferably 1G-25°C, for several minutes to several tens of cycles. The thus protected chromancarboxylic acid derivatives can be isolated or used in the alkylation reaction at the 2-position of the chroman ring in the c-6 step without being isolated.

Step 0-6 is a step for producing a chroman carboxylic acid derivative Ma4I having a protected hydroxyl group at the 6-position of the chroman ring and FL1' at the 2-position of the chroman ring, as desired.
Chromancarboxylic acid Q3 having a protected hydroxyl group in position
After treating 1 with a base in an inert solvent to generate a carbanion in the reaction solution, the general formula B 1 ' , bromine, iodine, etc.) or an ionanulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy). achieved by.

Examples of the ring group used include methyllithium, n
- organolithium compounds such as butyllithium, t-butyllithium, phenyllithium; lithium dialkylamides such as lithium diimprobylamide, lithium dicyclohexylamide, lithium isopropyl cyclohexylamide, etc.; or lithium hydride;
Examples include alkali metal hydrides such as sodium hydride and potassium hydride, but preferably organic lithium compounds or lithium dialkylamides.

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

In the reaction with ;O'C to 60°C, the time required for the reaction is 30 minutes to 2 hours in the first stage and 1 hour to 24 hours in the second stage.

0-7 to C-11 Each step corresponds to A-1 to A-5 steps, respectively, and the target compound f'l (w:
>OH2,Rki11) is produced.

In addition, if desired, the target compound fg(
W: >OH2, R1=H) can be produced.

Method D This method has already been proposed by the present inventors in a patent application filed in 1982-156.
This method is described in detail in No. 907 (abbreviated as No. 2), and is advantageously used to produce a compound in which W is a carbonyl group in the general formula (1). By this method, as shown below, compound (2) is obtained as the target object, edge (W:>-0)
, guided by. (D-1→D-4) (2; ]) In the above formula, R", R2, R3, n', R", A,
X and n have the same meanings as described above, and (1
1(W:,)-〇) represents a thiazolidine derivative in which W is a carbonyl group.

In this step, acetophenone derivatives (2) are reacted with a nitro compound in the presence of an organic base such as pyrrolidine, piperidine or morpholine to produce 4-oxochroman derivatives αe having a nitrophenoxy group.

D-2, D-3, D-4 Each step corresponds to A-3, A-4, and A-5 steps, respectively, and as described above, the target compound in which W is a carbonyl group, (! 2(W:>=O) is produced.

Method E Method E is advantageously used to produce a compound of the general formula (11) in which W is a carbonyl group and has a substituent R1' at the 2-position of the chroman ring. , the compound υ is guided to an intermediate body (E-
1→E-7) Chromonecarboxylic acid obtained in step C-3
9 (c) Earth 4z Chang (L) (w:')-〇) type αD is 0-
Under conditions milder than those used in step 4, only the double bond formed by the carbon atoms at the 2nd and 3rd positions was reduced (E-
1) step; and each step of E-2 to B-7;
Consisted of. In the formula, R1', B2. B4.
R5゜R10, and B have the same meanings as described above, and B2 represents a protected carbonyl group.

Each step will be explained in detail below.

Step E-1 is a step of obtaining 4-oxochromancarboxylic acids H from chromonecarboxylic acid 1Rα1). Catalytic reduction is used as the reduction method. Examples of the catalyst used in the catalytic reduction include palladium-carbon, Raney nickel, and platinum oxide, but palladium-carbon is preferable. The hydrogen pressure is from 1 atm to 100 atm, preferably from 1 atm to 6 atm. Examples of solvents include alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, amides such as dimethylformamide and dimethylacetamide, and organic acids such as acetic acid. Mention may be made of water and mixtures of these, with amides being preferred. Reaction conditions such as reaction temperature and reaction time vary depending on the raw materials and solvent used, but are usually room temperature to 50°C,
Preferably at room temperature to 40° C. for several minutes to several days, preferably about 30 minutes to about 20 hours.

Step E-2 is a step of protecting the carbonyl group of 4-oxochromancarboxylic acids, if desired.
It is desirable to carry out this protection prior to the alkylation reaction at the 2-position of the chroman ring in four steps. The protecting group is not particularly limited as long as it is a normal carbonyl group protecting group, and the oxo compound may be converted into protected enols such as enol ethers or enol esters, but It may be converted into cyclic or non-cyclic 4≠Kyosho≠=sha≠扛#ketone acetals or ketone dithioacetals, and conversion to ketone dithioacetals is preferred. Chromancarboxylic acids having a protected carbonyl group←l [wherein R2, B4.
R5 and B1 have the same meanings as described above,
B2 represents the formula -B5-B4-83-, B3 represents an oxygen atom or a sulfur atom, preferably a sulfur atom, and B4
For example, the formula -(OH2)2 v formula -(an2)5-
.

Formula -(CH2)4- or formula -0H2-OH=OH-
OH2-(cis), preferably formula -(CH2)2-
Or the formula = (CH2)5-ρ and the formula -(OH2)3-
shows. ] is usually produced using 4-oxochromancarboxylic acids αl and ethylene glycol, 1,3-propanediol, 1,2-ethanedithiol, 1,3-propanedithiol or cis-2-butene-1,4
-like diol 1l-B5-B4-B3-)1
(In the formula, B3 and B4 have the same meanings as described above.

), preferably 1,3-propanedithiol, in the presence or absence of a catalyst. As the catalyst,
Lewis acids such as boron trifluoride, its ether complex, its acetate complex, aluminum chloride; or inorganic acids such as hydrochloric acid, sulfuric acid; acetic acid, succinic acid, fumaric acid, maleic acid, para-toluenesulfonic acid, or methanesulfone Examples include organic acids such as acids, but Lewis acids are preferred, and acetic acid complex salts of boron trifluoride are particularly preferred. It is not necessary to use a solvent, but if a solvent is used,
Examples of the solvent include aromatic hydrocarbons such as benzene and xylene, halogenated hydrocarbons such as chloroform and dichloromethane, and preferably halogenated hydrocarbons such as chloroform. Compound ■ and H
-B3-B4-B6-H ratio is not particularly limited, but
Slightly more than equimolar excess of H-B3-B with respect to compound o9
4-B3-H is preferably used. Preferably compound 0
1 to 2 moles of H-B3-B4-B3-11. The ratio of compound 01 and catalyst is not particularly limited, but is 1 to 4 moles of catalyst per 1 mole of compound Ql. Reaction conditions such as reaction temperature and reaction time vary depending on the raw materials and type of solvent used, but are usually 0.
C. to 100" C1, preferably 10.degree. to 40.degree. C., for several minutes to several days, preferably for 1 hour to 30 hours.

Step E-3 is a step in which the phenolic hydroxyl group at the 6-position of the chroman ring of the oxochroman carboxylic acid (a) protected at the 4-position of the chroman ring is optionally protected. It is preferable to carry out this protection prior to the alkylation reaction at the 2-position of the ring.

(2B) Protecting groups for hydroxyl groups R buttons include the usual protecting groups for phenolic hydroxyl groups, such as benzyl groups which may be methoxy, and acyl groups such as acetyl and benzoyl, potassium hydride, hydrogen In the presence of bases such as alkali or alkaline earth metal hydrides such as calcium chloride, and alcolades of alkali metals such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, chloromethyl methyl ether, etc. This is achieved by using an alkylating agent such as alkoxyalkylating agent such as alkoxyalkylating agent or benzyl halide. In this reaction, examples of solvents include ethers such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane and heptane, dimethylformamide and dimethyl Examples include amides such as acetamide, sulfoxides such as dimethyl sulfoxide, and sulfones such as sulfolane. The ratio of the compound c2α and the alkylating agent is not particularly limited, but it is preferable to use an equimolar or excess amount of the alkylating agent with respect to the amount of the alkylating agent, and preferably the alkylating agent is The amount of the agent is 1 to 2 moles.

Reaction conditions such as reaction temperature and reaction time are as specified in Table 14.

The thus protected chromancarboxylic acids Qυ can be isolated or used in Step E-4 without being isolated.

Step E-4 is a process for producing chromancarboxylic acids (221) having a hydroxyl group protected at the 6-position of the chroman ring, a carbonyl group protected at the 4-position of the same term, and R1' at the 2-position of the same term, as desired. , a hydroxyl group protected at the 6-position of the chroman ring,
Chromancarboxylic acids (2+1) having a protected carbonyl group at the 4-position of the same term are treated with a base in an inert solvent to generate a carbanion in the reaction solution, and then the general formula R'' -
X' (In the formula, 1/ indicates the same meaning as mentioned above,
' represents a salt, a halogen atom such as bromine or iodine, or a ionasulfonyloxy group such as methanesulfonyloquine, ethanesulfonyloxy, benzenesulfonyloxy or p-)luenesulfonyloxy. ) is achieved by reacting a compound having

Bases used include, for example, methyllithium, n
-organolithium compounds such as butyllithium, 1,-butyllithium, phenyllithium; lithium dialkylamides such as lithium diisopropylamide, lithium dicyclohexylamide, lithium isopropyl cyclohexylamide, etc.; or lithium hydride, hydride Alkali metal hydrides such as l.lium and potassium hydride can be mentioned, but organic lithium compounds or lithium dialkylamides are preferred.

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

The reaction temperature is determined by the generation of anions in the first stage, and the time required for the reaction is 30 minutes to 2 hours in the first stage, and 1 hour to 24 hours in the second stage.

In addition, if desired, using chromancarvone H'$Gu in which R1 is a hydrogen atom, a reduction reaction according to Step E-5 and each reaction shown below can be carried out directly without going through Step E-4. By carrying out, the target compound where R1 is a hydrogen atom, history (w: )-〇, R,1:H)
・ Can be manufactured.

Step E-5 is a step of reducing chroman-2-carboxylic acids (221) to the corresponding alcohols (c) according to step A-1, and examples of the reducing agent include lithium aluminum hydride and vitride. (Sodium bis[2-methoxy ethoxy] aluminum hydride) and the like are used.

Examples of the solvent used in the reduction reaction include ethers such as diethyl ether, tetrahydrofuran, and ethylene glycol dimethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, hexane,
Examples include aliphatic hydrocarbons such as heptane, cyclohexane, petroleum ether, ligroin, and ethylcyclohexane.

Although there is no particular limitation on the ratio of the compound) and the reducing agent, it is preferable to use a slight excess of the reducing agent with respect to the compound portion Q2. Preferably, the amount is 1 to 2 moles per 2211 moles of the compound (2211 moles).The reaction conditions such as reaction temperature and reaction time are based on the raw materials used, and the alcohols ( This is a step of introducing a group +No2 into compound 9. This step is usually a step of introducing a group +No2 into compound 9. ethoxide, an alkali metal alkoxide such as potassium tert-butoxide, preferably sodium hydride, or sodium ethoxide to form the compound (c) into the corresponding alkoxide;
This is achieved by reacting this with a compound having the general formula X-()No,2 (wherein, X has the same meaning as described above).

In this reaction, examples of the solvent include ethers such as diethyl ether, tetrahydrofuran, and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, aliphatic hydrocarbons such as hexane and heptane, dimethylformamide, Amides such as dimethylacetamide, sulfoxides such as dimethyl sulfoxide, and sulfones such as sulfolane can be used, but amides are preferably used. Compound C! There is no particular limitation on the ratio of 5 and base, but for compound □□□,
It is better to use a slight excess of base, preferably 1 to 2 moles of base per mole of compound (2311).The ratio of compound (231 to compound 10 mol.Reaction conditions such as reaction temperature and reaction time vary depending on the raw materials and solvent used, but are usually 30° to 100 η.
It takes several minutes to several hours.

The nitro compound 24 having a protected carbonyl group at the 4-position of the chroman ring obtained in this step is D-2, D-3,
The target compound (,,!2
(W: >-o), but the deprotection reaction regarding the 4-position of the chroman ring may be carried out at any of the above steps. For example, as one of the preferred methods, E
The process shown in -7 can be mentioned.

Step E-7 is a step in which a nitro compound (241) having a protected hydroxyl group at the 6-position of the chroman ring and a protected carbonyl group at the 4-position is deprotected as desired. In this step, Usually, a deprotection reaction at position 4 is carried out, but
By setting radical reaction conditions, it is possible to simultaneously achieve deprotection of the 6-position.

The deprotecting agent is not particularly limited, but common deprotecting agents include protonic acids such as hydrochloric acid and sulfuric acid; boron trifluoride, its ether complex salts, its acetate complex salts, and Lewis acids such as aluminum chloride; Especially when B6 is a sulfur atom,
Heavy metal salts, heavy metal oxides or heavy metal oxides;
or a mixture of two or three of these;
Heavy metal ions include silver, cadmium, divalent mercury, divalent copper, and trivalent thallium; counter ions to heavy metal ions include halogen ions such as chlorine, bromine, and iodine, nitrate ions, and peroxide ions. Other examples include iodine, sulfuryl halides such as sulfuryl chloride, and N-halimides such as N-chlorosuccinimide and N-promosuccinimide. , preferably mercuric chloride, or mercury oxide, or mixtures thereof, especially mixtures thereof. The solvent used is methanol,
Ethanol propatool Alcohols such as isoproptool, ketones such as acetone and methyl ethyl ketone, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, ethers such as tetrahydrofuran and dioxane, and organic acids such as acetic acid. , nitriles such as acetonitrile, and water,
Also, mixed solvents thereof can be mentioned.

The ratio of compound Q and deprotecting agent is not particularly limited, and is usually C! 1 to 10 moles of deprotecting agent per 411 moles,
The amount is preferably 1 to 4 moles.

Reaction conditions such as reaction temperature and reaction time vary depending on the raw materials and solvent used, but are usually room temperature to 100 ℃.
C., preferably 40 to 80.degree. C., for a few minutes to several hours, preferably 0.5 to 4 hours.

Thereafter, using the obtained compound blank, the target compound,
History (W; )=o) f) Manufacture is achieved.

Method F Method F is a method for preparing a target compound in which W is a methylene group, (Q(W
;〉. I42) may be advantageously used to prepare the compounds 06) and 1 shown in the description of process D, in which W is a carbonyl group.

By Kenpo, the compound cape is an intermediate (
6). (F-1→F-5) In the formula, R1, B2
．． B3. R4, R5, and n have the same meanings as described above, and 'view' indicates that the hydrogen atom is excluded from the definition of R3.

Step F-1 is a step of reducing the 4-oxochroman compound Oe having a nitro group to the corresponding 4-hydroxy compound (c). Examples of the reducing agent include reducing agents such as sodium borohydride and k-selectride, and the reduction reaction is particularly preferably achieved with sodium borohydride.

The reaction between compound (161 and boron hydride) IJium is usually carried out in a solvent. Examples of the solvent include alcohols such as methanol, ethanol, bronokol, phthanol, and ethylene glycol monomethyl ether, and ethers such as tetrahydrofuran and dioxane. The molar ratio of the compound (161 and boron hydride) to IJium is not particularly limited, but
It is advisable to use an excess of sodium borohydride relative to compound Q61. Preferably, the amount is 1 to 20 mol per 1611 mol of the compound.

Reaction conditions such as reaction temperature and reaction time depend on the raw materials used,
The reaction usually takes place at 0 to 100° C. for 1 to about 20 hours, although it varies depending on the solvent and the like.

In the F-2 step, as desired, the hydroxyl, cycloisomer Q6
This is the step of acylating 1.

Compound (c) can be converted into the desired acylated compound by reacting with an acylating agent such as an acid chloride or an acid anhydride.

The reaction is usually carried out in a solvent. Solvents 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 include chlorogenated hydrocarbons such as pyridine, organic bases such as triethylamine, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethyl sulfoxide, and sulfones such as sulfolane. It will be done.

The ratio of compound (a) and acylating agent is not particularly limited, but
It is preferable to use the acylating agent in a slightly more than equimolar excess with respect to compound (a). Preferably, the amount of the acylating agent is 1 to 10 mol per 1 mol of the compound. Reaction conditions such as reaction temperature and reaction time vary depending on the raw materials and type of solvent used, but are usually 0 to 100''C and several minutes to about 20 hours.

Step F-3 is a step for producing 2H-chromenes L2η by eliminating water from the 4-hydroxychroman compound ge having a nitro group.

The elimination reaction is accomplished in the presence or absence of a dehydrating agent or catalyst.

As a dehydrating agent or dehydrating catalyst, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, organic acids such as acetic acid, succinic acid, and maleic acid, and sulfonic acids such as paratoluenesulfonic acid, naphthalenesulfonic acid, and methanesulfonic acid. acids,
Examples include inorganic salts such as ammonium chloride and calcium chloride, phosphorus pentoxide, polyphosphoric acid, silica gel, and alumina, but organic acids such as acetic acid and sulfonic acids such as para-toluenesulfonic acid are preferred.

It is not necessary to use a solvent during the elimination reaction, but if a solvent is used, alcohols such as methanol, ethanol, isopropanol, acetone, methyl
Ketones such as ethyl-ketone, ethers such as ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane, cyclohexane and heptane, dichloromethane, Hydrocarbons such as chloroform, organic acids such as acetic acid and propionic acid,
Examples include organic bases such as pyridine and triethylamine, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, and water. Preferred examples include benzene and the like. Examples include aromatic hydrocarbons and organic acids such as acetic acid. When using a dehydrating agent or a dehydrating catalyst, compound Q6) and the dehydrating agent,
The ratio of the dehydrating agent to the dehydrating catalyst is not particularly limited, but is usually 1 to 10 moles, preferably 01 to 3 moles, per 001 moles of the compound. Reaction conditions such as reaction temperature and reaction time vary depending on the raw materials and type of solvent used, but are usually 0 to 100 m
”c, from a few minutes to about 20 hours.

Step F-4 is a step for producing 2H-chromenes +271 by converting 4-acyl having a nitro group.

The elimination reaction is accomplished in the presence or absence of a deoxidizing agent or deoxidizing catalyst.

Hydrochloric acid, sulfuric acid, nitric acid,
Inorganic acids such as phosphoric acid, organic acids such as acetic acid, succinic acid, maleic acid, sulfonic acids such as para-toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, inorganic salts such as ammonium chloride, calcium chloride, organic bases such as pyridine, triethylamine,
Examples include silica gel and alumina, and preferred examples include organic acids such as acetic acid and sulfonic acids such as para-toluenesulfonic acid.

In the deacidification reaction, it is not necessary to use a solvent, but if a solvent is used, alcohols such as methanol, ethanol, and isopropanol, ketones such as acetone and methyl ethyl ketone, ether, and tetrahydrofuran are used. , ethers such as dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, aliphatic hydrocarbons such as hexane, cyclohexane and heptane, 10-genated hydrocarbons such as dichloromethane and chloroform, acetic acid. , organic acids such as propionic acid,
Organic bases such as pyridine and triethylamine, amides such as dimethylformamide and dimethylacetamide, and dimethylene.

Preferred examples include sulfoxides such as sulfoxide, sulfones such as sulfolane, water, etc., aromatic hydrocarbons such as benzene, or organic acids such as acetic acid.

When using a deoxidizing agent or deoxidizing catalyst, compound c2
The ratio of 81 to the deoxidizing agent or deoxidizing catalyst is not particularly limited, but usually the deoxidizing agent or deoxidizing catalyst is 0.001 to 10 mol per 1 mol of the compound, preferably,
01 to 3 moles. Reaction conditions such as reaction temperature and reaction time vary depending on the raw materials used and the type of solvent, but are usually 0 to 120°C, preferably 40° to 120°C.
00° C. for several minutes to several days, preferably 10 minutes to 10 hours.

In the F-5 step, 2H-chromenes (5
This is a process for producing chromans (6) having an amine group by simultaneously reducing the nitro group and carbon-carbon double bond of ).

A catalytic reduction method is preferably used for the reduction reaction. Examples of the catalyst used in the catalytic reduction include palladium-carbon, Raney nickel, and platinum oxide, but palladium-carbon is preferable. The hydrogen pressure is from 1 atm to 100 atm, preferably from 1 atm to 6 atm. As a solvent,
Examples include methanol, ethanol, and mixtures of these. The reaction temperature and reaction time vary depending on the raw materials and solvent used, but are usually at room temperature to 50''C for several minutes to about 20 hours.

Thereafter, the production of α-no-10-genocarboxylic acid derivatives (7) is achieved by using the obtained compound (6) in step A-4.

In addition, F-1, F-2, F-3, F-4°F-5, A-
4 and/or the final step of producing the desired thiazolidine derivative, if desired, the intermediate (c)
, @, @, (6).

and/or (7) may be carried out without isolation.

Furthermore, the steps shown in Method F, for example, are not limited to the order shown. That is, for example, a thiazolidine derivative whose initial group is a nitro group possessed by a compound Oe in which the 4th position of the chroman ring is a carbonyl group, especially a compound 0j in which Y and Z are both oxygen atoms, and a compound in which W is a methylene group (□ □□.

In the formula, R', 1N2. R3, R'', R', R
5 and n have the same meanings as described above.

In this step, one of the target compounds, W, is a carbonyl group,
A thiazolidine derivative in which both Y and Z are oxygen atoms is reduced with a reducing agent such as sodium borohydride or K-selectride, particularly sodium borohydride, to give the desired effect. ) is converted into thiazolidine derivative 04, the details of which are the same as those described in the previous issue 2.

In this step, I(-1, then -10R at the 4-position of the chroman ring
3' (in the formula, R5!'' has the same meaning as described above) is removed to form a thiazolidine derivative C351 in which the 3 and 4 positions of the chroman ring are carbon-carbon double bonds.

The details are F-3 and/or F in the present invention.
This is similar to the steps - and -4.

This step reduces the double bond next to H-2), which is one of the target compounds (1
A thiazolidine brocade conductor C3lI+) in which W is a methylene group and Y and Z are both oxygen atoms is produced. The details are as follows: F-5 step in the present invention (however, F-5 step
In Step 5, the reduction reaction of the nitro group is also carried out at the same time. ).

The thiazolidine derivatives according to the present invention in which R3 and/or R3' are hydrogen atoms can be converted into corresponding esters by conventional methods.

A method for producing a thiazolidine derivative fil constituting the present invention, namely B, O, E, F, G and
Among the H methods, the preferred one is 0. E.

Methods F and H; more preferred are methods C9F and H; particularly preferred are methods F and (2).

In the compound (+1), the carbon atoms at the 2-position of the chroman ring and the 5-position of the thiazolidine ring are asymmetric carbon atoms, and each isomer based thereon is also included in formula (1).

By the method according to the invention, preferred compounds can be produced, for example, having the structural formulas shown in the following table.

(Abbreviations: For example, 1-Me, butyl, etc. are (5B
) The present invention will be described in more detail below with reference to Examples and Reference Examples.

Abbreviations related to NMR spectra, nd, indicate other signals.
Or overlapped with the signal of solvent etc., Example 1 (0-4
) Ethyl 6-hydroxy-5,7,8-) IJ methylchromone-2-carboxylate 14.9 to acetic acid 320
m1, in the presence of 35 g of 10% palladium on carbon,
Catalytic reduction was carried out at 60 to 65° C. for 1 hour under a hydrogen pressure of 3 atm. The catalyst was poured into each household, and the filtrate was poured into water to collect the precipitated white crystals. The melting point of the target product was 108-109°C.

NMR spectrum (δ, aDai3): 29m 1.28 (3H, t, J=7Hz).

2.01 (3Hl　s) + 2.17 (6H, S).

1.9-2.3 (2H, nd).

2.65 (2H, br, t, J=7Hz).

4.22 (2H, q, J=711z).

4.1-4.3 (IH, n.d.).

4.60 (IH, dd, J==7 and 4Hz) Example 2 (0-5) Ethyl 6-Medoxymethoxy5.7.8-) Ethyl 6-hydroxy-5,7,8-) IJ 5-IQ was added to a mixture of 143 g of methylchroman-2-carboxylate and 130 ml of dimethylformamide under a nitrogen stream.
Add 3 g of 55% oily sodium hydride (washed twice with cyclohexane) little by little at room temperature. After stirring at room temperature for 1 hour, ice-cool to 3-5° C. and dropwise add 5.6 g of chloromethyl methyl ether. After the addition is complete, stir at room temperature for 1 hour.

The reaction mixture is poured into ice water and extracted with cyclohexane.

The extract was washed with water and dried over anhydrous sulfuric acid. 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 target compound.

Rf value of silica gel thin layer chromatography = 041 (
Developing solvent; benzene: ethyl acetate-20: NMR spectrum (δ, cnai3): 29m 1.27 (3H, t, J=7) 1z).

2.0-2.4 (2H, nd).

2.15 (3H, 8).

2.16 (3H, 8).

2.2 (3H, s).

2,64 (2H, br, t, J-7Hz)
+3.61 (3H, S).

4.117 (2H, s).

Example 3 (C-6) 4.6 g of diisopropylamine 1 of tetrahydrofuran
A solution of 2 g of n-butyrrhizic-5,7,8-)dimethylchroman-2-carboxylate in 10 ml of tetrahydrofuran was added dropwise to the 00 ml solution at -20 to -10°C, and the mixture was stirred at the same temperature for 2 hours. 10 g of isobutyl bromide was added dropwise and left overnight at room temperature, then heated at 40"C for 4 hours. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added, and the organic layer was separated, washed with water and poured over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (
The desired product was obtained by using an eluent (hexane:ethyl acetate = 7:1).

Rf value of silica gel thin layer chromatography 20.59
(Developing solvent; hexane: ethyl acetate: toluene = 3:1
:1) NMR spectrum (δ ODO flood, ): ppm+ 0.9-1.3 (9H, nd).

1.4-2.7 (7H, nd).

2.10 (3H, s).

2.16 (3H, s).

2.20 (3H, s).

3.60 (3H, 8).

4.12 (2H, q, J=7tlz).

4.86 (2H, s).

Example 4 (g-1) ethyl 6-hydroxy-5, 8-) IJ methylchromone-2-carboxylate catalytic reduction in the presence of 16 g of carbon at a hydrogen pressure of 5 atm and at 50 to 60°C for 7 hours did. The catalyst was removed, the p solution was poured into a large amount of water, and the precipitated crystals were collected.

The obtained crystals were recrystallized from ethyl acetate to obtain the target compound.

Melting point: 120-121°C NMR spectrum (δ, 0DO113): 99
m 1, 26, (3H, t, J:=7+Tz)
.

2, 23 (fiH, s).

2, 52 (3H, s).

2,98 (2H, d, , T==7Hz)
.

4, 24 (2H, q, J==7Hz).

4, 83 (IH, s).

4, 94 (IH, t, J=7Hz).

Extract the P solution containing the above target compound with ethyl acetate,
The extract was dried with anhydrous sodium sulfate, and then the solvent was distilled off.
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-hydroxyhydroxyl was obtained from the second fraction.5. 7. 8-) Dimethylchroman-2-carboxylate was obtained.

Melting point: 13B-144°C.

Example 5 (E-2) Ethyl 6-hydroxy-5. 7. 8 = trimethyl-4-oxochroman-2-carboxyle) 1
6.6g, 1. 3-Propanedithiol9.7.
20 ml of boron trifluoride acetate complex salt (40% boron trifluoride) was added dropwise to a solution of 500 mg of chloroform of No. 9 under water cooling, and the mixture was left at room temperature for 24 hours. The reaction mixture was poured into ice water, neutralized with potassium carbonate, extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain the target compound.

Melting point: 186-188℃ NMR spectrum (δ,, ODOρ3): 99m 1, 35 (3H, t, J==7H2).

t8-2.4 (2H, nd).

2, 18 (6H, 8).

2, 5-2.9 (3H, nd).

2,80 (3H,s).

3, 0-3.5 (3H, m).

4, 31 (2H, q, J near Hz).

4,50 (IH, s).

4, 79 (I H, dd, J=2 and 10
1■z).

Example 6 (E-3) Ethyl spiro[6-hydroxy-5. 7. 8-
Trimethylchroman-4.2'-[1,31 dithiane]
After the mixture was subjected to ultrasonic treatment 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 value of silica gel thin layer chromatography 20, 21
(i opener; hexane: ethyl acetate = 5: NMR spectrum (δ, CDCQ3): 99 m 1, 34 (3H, t, J = 7 Hz).

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 (1r-i, nd).

4.89 (2H, S).

Example T (E-4 and E-5) 3 g of diisopropylamine 90 m of tetrahydrofuran
1 solution at -60°C to -so°C. Ethyl spiro[6-medoxymethoxy5. Otsu8-trimethylchroman-4,2'-(1,3
) 4.8!9 was added and stirred for 10 minutes, then 4.1 g of isobutyl bromide was added, stirred for 30 minutes, stirred at room temperature for 1.5 hours, and further 3 g of inbutyl bromide was added. It was heated at 40°C for 5 hours. The reaction mixture was cooled to -50°C, 0.6 g of lithium aluminum hydride was added, and the mixture was stirred at room temperature for 1 hour. Benzene, ethyl acetate, and water were added to the reaction mixture, and the organic layer was separated, 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: hexane:ethyl acetate-5:1).
) to obtain the target compound.

Rf value of silica gel thin layer chromatography = 0.16
(Developing solvent; hexane: ethyl acetate-5: NMR spectrum (δ, CDCl13): 29 m 1.03 (3H, d, J = 6 Hz).

1.04 (3H, d, J=6Hz).

1.70 (2H, d, J = 6Hz).

1.8-2.3 (3H, nd).

2.08 (3H, S).

2.20 (31-I, s)'.

2.3-3.0 (4H, nd).

2.91 (3H, S).

3.05-3.95 (51J, n.d.).

3U2 (3H,s,).

4.88 (2H, s).

Example 8 (E-s) 4 ml of ethanol was added to a mixture of 720 ml of -y, and spiro[2-isobutyl-6-medoxymethoxy5.7.8-)limethylchroman-4°2'
-(1,3)dithiane]-2-ylmethanol 3.2g
A solution of 20 ml of tetrahydrofuran was added.

After the solvent was distilled off to dryness under reduced pressure, 30 ml of dimethylformamide was added, and the mixture was heated at 40'C for 1 hour under reduced pressure. Add 10g of p-nitrochlorobenzene and heat at 50℃ for 2 hours.
heated for an hour.

Water was added to the reaction mixture, extracted with benzene, and the benzene solution was washed twice with water and then 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-6=1
) to obtain the target compound.

Rf value of silica gel thin layer chromatography = 054 (
Developing solvent; hexane:ethyl acetate-2=NMR spectrum (δ, cnan3): 29m 1.02 (3H, d, J=6Hz).

1.09 (3H, d, J=6Hz).

1.83 (2H, d, J=6Hz).

1.8-2.3 (3H, nd).

2.11 (3H, s).

2.22 (3H, s).

2.3-2.9 (3H, nd).

2.89 (3H, s).

3.0-3.7 (3H, nd).

3.62 (3H, l1l).

3.92 (IH, d,, r2 4.5 FIz).

4.50 (IH, d, J = 4.5EIz).

4.90 (2H, s).

6.90 (2H, d, J=4.51 (Z,).

8.17 (2H, d, J=4.5Hz).

Example 9 (B-7) Spiro[2-isobutyl-6-medoxymethoxy5.
Otsu8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4,2'-[1,3]dithiane:]3,3
g, 4 g of mercuric chloride, 1.4 g of mercuric oxide, and 1
A mixture of 3 aml of 0% aqueous methanol was heated under reflux for 2 hours. Add ether to the reaction mixture, filter out insoluble matter,
After washing the P solution with a saline solution and then an aqueous ammonium sulfate solution, it was dried over anhydrous sulfuric acid (IJ). The solvent was distilled off, and the residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate = 4:1) for separation and purification to obtain the target compounds (11 and (2)).

Silica gel thin layer chromatography (developing solvent; hexane: ethyl acetate-2=1) Rf value of (1) = 048 Rf value of (2) = 04O NMR spectrum (δ, ODOρ6): 99m fl) 1.01 (6H , d, J=6Hz).

1.84 (2H, s).

1.6-2.1 (IH, nd).

2.12 (3H, s).

2.27 (3H, s).

2.58 (3H, S).

2.81 (IH, d, J=19Hz).

3.00 (IH, d, J=19Hz).

3.62 (3H, s).

4.14 (IH, d, J=11Hz).

4.25 (IH, d, J=1111z).

4.8'9 (2H, s).

6.95 (2H, d, J=4.5Hz).

8.20 (2H, d, J=4.5Hz).

(210,9g (3H, d, J=6Hz)'.

1.00 (3H, d, J=6Hz).

1°8 (1(2H, d, , r=snz).

165-2.1 (IH, nd).

2.13 (3H, S).

2.23 (3H, S).

2.57 (3H, s).

2.82 (IH, d, J-141'lz).

3.00 (IH, d, J=1411z).

4.13 (IH, d, J=12Hz).

4.27 (IH, d, J=12Hz).

4.66 (IH, s).

11i, 95 (2H, d, J=9H2).

8.19 (2H, d, J=9Hz).

Example 10 6-hydroxy-2-ynbutyl-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)
4-Oni/L59. 3 oml of pyridine.

3 g of acetic anhydride was added to the mixture, and the mixture was stirred at room temperature for 35 hours. The reaction mixture was concentrated, water was added, extracted with ethyl acetate and benzene, and the extract was diluted with anhydrous sulfuric acid).
It was dried with Jum. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: hexane:ethyl acetate-5=1) to obtain the target compound.

Rf value of silica gel thin layer chromatography = 042 (
Developing solvent; hexane:ethyl acetate=2=1).

NMR spectrum (δ, cncp3): 99m 1.01 (6) (, d, J=6h).

1.7-2.2 (3H, nd).

2.09 (3H, s).

2.12(3I(,S).

2.33 (3H, S).

2.42 (3H, s).

2.91 (2H, AB type, J=1811z).

413 and 4.25 (2H, AB type, J=9Hz
).

6.95 (2H, d, J==9Hz).

g2Q(2t(,d,,r29Hz).

Example 11 6-acetoxy-2-isobutyl-5. Otsu 8 ~ Trimethyl-2-(4-nitrophenoxymethyl)chroman-
Dissolve 1.4.9 of 4-one in 35 ml of methanol,
3 at a hydrogen pressure of approximately 1 atm in the presence of 0% palladium on carbon-11.
I got my time back. After removing the catalyst, the solvent was distilled off under reduced pressure to obtain the desired product.

af value of silica gel thin layer chromatography = 054 (
Developing solvent; ethyl acetate).

NMR spectrum (δppm, cnan3): 0
．． 97 (6H, d, J=6Hz).

1.6-2.2 (3H, nd).

2.08 (3H, S).

2.14 (3H, S).

2.32 (3H, 8).

2.42 (3H, S).

2.14 and 3.02 (2H, AB type, J216FI
z).

3.2-3.7 (2H, br, s).

394 and 4.06 (2H, AB type, J=9Hz)
.

6.58 (2H, d, J=9■Z).

6.73 (2H, d, J=9Flz).

Example 12 (D-3) 6-acetoxy-2-(4-aminophenoxymethyl)
-2-isobutyl-5,7,8-)dimethylchroman-
4-one 1.1g, acetone 2aml! To the mixture were added 15 me concentrated hydrochloric acid, 0.8 g of sodium nitrite and 0.3 ml of water, and then 4 g of ethyl acrylate at room temperature under a nitrogen stream. At room temperature, 0.1 g of cuprous oxide was added and stirred for 1 hour. Water was added to the reaction mixture and extracted with benzene. The extract was washed with water, dried over anhydrous sulfuric acid (IJ), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: hexane:ethyl acetate-5:1) to obtain the target compound.

Rf value of silica gel thin layer chromatography is 2074 (
Developing solvent; hexane: ethyl acetate = 1 = 2).

NMR spectrum (δ, cncc3): pm 0.98 (6H, d, J=6Hz).

1.25 (3H, t, J=7Hz).

1.5-2.2 (3H, nd).

2.08(3)1. s).

2.13 (3H, s).

2.32 (3H, S).

2.42 (3H, s).

2.78 and 3. (li (2H, A, B type, , T
=171Tz).

2.8-3.5 (2T(,nd).

3.8-4.5 (5H, nd).

6.82 (2H, d, J=9Hz).

7.11 (2H, d, J=9Hz).

Example 13 (D-4) Ethyl 3-[4-(6-acetoxy-2-isobutyl-5,7,8-)rifthyl-4-okynechroman-2-
ylmethoxy)phenyl]-2-chloropropionate 05 g, thiourea 0.2 g and sulfolane 0.851
The mixture is heated at 12G-135°C for 4 hours under nitrogen flow. Then, add 1 ml of concentrated hydrochloric acid, 1 ml of water to the reaction mixture,
A mixture of 5 ml of ethylene glycol monomethyl ether was added, and the mixture was further heated under reflux for 6 hours. The reaction mixture was poured into water, 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 subjected to silica gel thin layer chromatography (developing solvent: hexane:
Ethyl acetate (1:1) to obtain the target compound.

Softening point near 0-78°C NMR spectrum (δppm, 0naQ3): 0
．． 97 (6H, d, , T=6Hz).

1.5-2.1 (3H, nd).

2.12 (3H, s).

2.21 (3H, s).

2.53 (3H, s).

2.77 and 2.99 (2H, AB type, J==46H
z).

2.8-3.2 (IH, nd).

3.41 (IH, dd, J:4 and 14H2).

4, [+6 (2H, AB type, J=1 fJFIz)
.

4.43 (IH, dd, J=4 and 9H2).

4.6-5.3 (I H, br, s, disappeared by addition of heavy water).

6.81 (2H, d, J-=9Flz).

7.12 (2H, d, J-=9Hz).

8.7-9.3 (I H, br, s, , disappeared by addition of heavy water).

Example 14 (D-1) 2.5-dihydroxy-3,4,6-drimethylacetophenone 3.9 g, 4-nitrophenoxyacetone 39
After leaving 2.0 g of pyrrolidine and 15 g of toluene at room temperature for 2 days, dilute hydrochloric acid was added to the reaction mixture and extracted with ether. The aqueous layer is further extracted with ethyl acetate, combined with the ether extract, and dried over anhydrous sodium sulfate.

The solvent is distilled off, hexane is added to the resulting residue, and the precipitated crystals are counted. The residue was further subjected to silica gel column chromatography (eluent: hexane:ethyl acetate-5:1), and then recrystallized from ethyl acetate to obtain the target compound.

Melting point: 199-204°C NMR spectrum (δ, nMso-d6): 9
9m 1.43 (3H, s).

2.01 (3r-r, s).

2.14 (3H, s).

2.46 (3H, s).

2.67 (IH, d, J=16Hz).

3.03 (IH, d, J=16Hz).

4.31 (2H, s).

7.19 (2H, d, J=9tTz).

7.92 (1H, S).

8.21 (2H, d,, r=9Hz).

Example 15 (D-1) =4-one a) 5-acetoxy-2-hydroxy-3,4°6
- After leaving a mixture of 17.7 g of dolimethylacetophenone, 14.6 g of 4-nitrophenoxyacetone, 7.59 pyrrolidine and 60'rnl of benzene at room temperature for 1 day,
The mixture was heated under reflux for 7 hours using a water separator. Water and ethyl acetate were added to the reaction mixture, and the organic layer was separated and dried over anhydrous sulfuric acid. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (eluent;
Hexane:ethyl acetate=2:1) K was added to obtain the target compound.

Rf value by silica gel thin layer chromatography =
0.17 (developing solvent; hexane:ethyl acetate-3=1
) NMR spectrum (δ, ODOρ3): 99m 1.56 (3H, s).

2.10 (6H, S).

2.36 (3H, s).

2.43 (3H, s).

2.70 (IH, d, J=15f(z).

3.06 (1H, d, r2 15Hz).

4.11 (IH, d, J=10Hz).

4.24 (IH, d, J=10FIz).

6.98 (2H, d, J=9Hz).

8.20 (2H, d, J=9Hz).

b) The mixture in a) in which piperidine was used instead of pyrrolidine was heated under reflux for 3 hours using a water separator.

5% hydrochloric acid was added to the reaction mixture, and the mixture was extracted with benzene. The extract was washed with water and dried with anhydrous sulfuric acid (IJum). af value and NMR of the target compound obtained by distilling off the solvent
The spectrum matched that in a).

c) The Rf value and NMrL spectrum of the target compound obtained in the same manner as in b) using morpholine instead of piperidine in b) were consistent with those in a).

d) In a), a mixture in which morpholine was used instead of pyrrolidine and toluene was used instead of benzene was heated under reflux for 1 hour, followed by Example 16 (D-1) in the same manner as in b). 4-t-butyl-2,5-dihydroxyacetophenone 2.0g, 4-nitrophenoxyacetone 1.9,9. The target compound produced from 1.0 g of pyrrolidine and 10 ml of benzene has the following physical properties.

Melting point: 205-209℃ NMR spectrum (δ double acetone) 2 pm 1.39 (3H, s).

1.53 (9H, s).

2.70 (IH, d, J=16.5Hz).

3.05 (I H, d, J=16.5tlz)
.

4.37 (2H, S).

6.80 (IH, s).

7.18 (2H, d, J=10Hz).

7.22 (IH, s).

8.22 (2H, d, J='1Otlz).

8.31 (IH, S, disappeared by addition of heavy water).

Example 17 7-t-butyl-6-hydroxy-2-methyl-2-(
4-nitrophenoxymethyl)chroman-4-one1.
A mixture of 7 g, 1 ml of acetic anhydride and 10 me of pyridine is left at room temperature for 1 day. The reaction mixture was poured into ice water, stirred for 2 hours, and then extracted with benzene. The organic layer is washed successively with 3N hydrochloric acid, water, saturated hydrogen carbonate, an aqueous IJ solution, and water, and dried over anhydrous sulfuric acid. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from benzene-ethyl acetate (about 10:1) to obtain the target compound.

Melting point: 82-84°C NMR spectrum (δ double acetone): 99m 1.33 (9H, 8).

1.57 (3H, S).

2.33 (3H, s).

2.82 (IH, d, J=16.5Hz).

3.13 (IH, d, J=16.5Hz).

4.42 (2H, s).

6.93 (1H, s).

7.25 (2H, d, J=9Hz).

7.44 (IH, s).

8.22 (2H1d, J=9Hz).

Example 18 (F-1) 6-acetoxy-4-hydroxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman 6-acetoxy-2,5,7,8-tetra Methyl-2-
(4-nitrophenoxymethyl)chroman-4-one L
8fi, methanol 15ml 1. To a mixture of 1 ml of benzene was added 160 μm of sodium borohydride under water cooling, and the mixture was stirred for 30 minutes. Pour the reaction mixture into ice water and dilute to 10%
After neutralizing with hydrochloric acid, the mixture was extracted with benzene, and the extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: benzene:ethyl acetate - 9:1), and the obtained crystals were recrystallized from a mixture of benzene and hexane to obtain the target compound. I got it.

Melting point: 139-141°C NMR spectrum (δ, ODO+!3): 99
m 1.56 (3H, s).

2.05 (6H, s).

2.0-2.4 (2H, nd).

2.19 (3H, s).

2.33 (3H, s).

4.10 (2H, AB type, J-9h) +5.0(
IH, dd, J=3 and 9frz).

7.03 (2H, d, J=91(z).

8.23 (2H, d, J=9Hz).

Example 19 (F-1) Chroman 6-acedoxy 7-t-butyl-2-methyl-2-(
4-nitrophenoxymethyl) chroma:/-4-one 3
A solution of 0 g of THF (20 ml) was added to a suspension of 0.3 g of sodium borohydride in methanol (10 m6) under water cooling and stirring.
). After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. Cool again on ice, make weakly acidic with 10% hydrochloric acid, and then extract with ethyl acetate. After washing the organic layer with water, it is dried over anhydrous sodium sulfate.

The crystals obtained by distilling off the solvent were recrystallized from benzene-petroleum ether to obtain the target compound.

Melting point: 194-201℃ NMR spectrum (δ single acetone) 2 pm 1.34 (9H, s).

1.5f] (3H, s,).

1.88 (I H, dd, J=13.5 and 9
Hz).

2.45 (I H, dd, J=13.5 and 6
Hz).

2.78 (IH, s, disappeared by addition of heavy water).

4.15 (2H, 8).

4.75 (1H, m).

6.62 (IH, S).

8,! H(1H,s).

7.15 (2H, d, J=9Hz).

8.20 (2H, d,, ■ = 9 Hz).

Example 20 (F-2) Chroman 7-t-butyl-4,6-dihydroxy-2=methyl-
2-(4-nitrophenoxymethyl)chroman 2.0g
3 ml of acetic anhydride was added to a mixture of 20 ml of pyridine and 20 ml of pyridine, and the mixture was heated at 50°C for 3 hours. The reaction solution was dissolved in benzene, washed successively with 3N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, and water, and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the target compound as a pale yellow oil.

AF value by silica gel thin layer chromatography: 0
．． 62 (Developing solvent; benzene: ethyl acetate = 5:1) NMR spectrum (δ double acetone) 2 pm 1.31 (9H,S).

1.55 (3H, s).

1.77 (3H, S).

2.0-2.3 (IH, nd).

2.27 (3H, S).

2.45-2.7 (IH, nd).

4.20 and 4.38 (2H, AB type + J 21
(l Hz) +5.85-6.10 (IH, m)
.

6.87(11(,S).

6.98 (IH, s).

7.20 (2H, d, J29Hz).

8.30 (2H, d, J=9Hz).

Example 21 (F'-4) 6-acetoxy-? -t-butyl-2-methychromene 4,6-diacedoxy7-t-butyl-2-methyl-
2-(4-nitrophenoxymethyl)chroman 2.4,
9. p-) A mixture of 01 g1 of toluenesulfonic acid hydrate and 50 ml of benzene is heated under reflux for 1 hour. Thereafter, the reaction solution is washed with a saturated aqueous sodium bicarbonate solution, then with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound as a yellow oil.

Rf value by silica gel thin layer chromatography = o
, ss (developing solvent; benzene: ethyl acetate = 10:
1) NMR spectrum (δ single acetone) 2 pm 1.27 (9H,s).

1.54 (3H, S).

2.27 (3H, s).

4.28(21(,S).

5.79 (IH, d, J-1 (ltlz).

6.52 (IH, d, J2 10Hz).

6.67 (IH, s).

6.76 (IH, s).

7.13(2H,d,,r29[(z).

8.20 (2H, d, J=9Hz).

Example 22 (F-3) Romene According to Example 21, 6-acetoxy-4-hydroxy-2,5,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman 160m9゜p-toluenesulfone The target compound produced from 10 mq of acid and 2 ml of benzene has the following physical properties.

Silica gel thin layer chromatography af value = 0.49
(Developing solvent: benzene:ethyl acetate-2 (1:1)N
MR spectrum (δ, ancu3): 99m 1.59 (3H,S).

2.03 (3H, s).

2.05 (3H, s).

2.09 (3H, S).

2.33 (3H, s).

tlo (2I+, AB type, J:9 [IZ).

5.13 (IH, d, J=IQHz).

6.73 (IH, d, J=10Hz).

6.96 (2H, d, J==9Hz).

8.22 (2H, d, J=9Hz).

Example 23 (F-5) 1 = - and - 6-acedoxy7-t-butyl-2-methyl-2-(
4-nitrophenoxymethyl)-2H at room temperature,
Reduction was carried out under a hydrogen pressure of about 1 atm for 10 hours. After removing the catalyst, the benzene solution is washed with a saturated aqueous solution of hydrogen carbonate, then water, and dried over anhydrous sulfuric acid.

The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (eluent: benzene) to obtain the target compound as a pale brown oil.

Rf value of silica gel thin layer chromatography = Q, t3
(MHFl solvent; benzene: ethyl acetate = 10 = NM
R spectrum (δ double acetone): 99m 1.30 (9H,S).

1.40 (3H, S).

1.7-2.2 (2H, nd).

2.27 (3H, S).

2.73 (2H, br, t, J=7Hz).

3.89 (2H, s).

3.7-4.5 (2H, br, disappeared by addition of heavy water).

6.50-7.05 (6H, m).

Example 24 (P-5) According to Example 23, 6-acetoxy-2,5,7°8
-tetramethyl-2~(4-nitrophenoxymethyl)
-2H-chromene 100'm9 methanol 2 ml
The target compound obtained by reducing the solution under hydrogen pressure of about 1 atmosphere in the presence of 20 m9 of 10% palladium on carbon has the following physical properties.

Melting point: 13B-140°C NMR spectrum (δ, CDCf13): 99
m 1.42 (3H, s).

2.00 (3H, s).

Approximately 2 (2H+m)+ 2.04(31(,S).

2.10 (3H, s).

2.31 (3H, s).

2.6 (2H, br, t, J=6Hz).

3.37 (disappeared with addition of 2H, br1 heavy water).

380 and 3.95 (2H, AB type, J=9Hz
).

6.62 (2H, d, J=7.5Hz).

6.78 (2H, d, J = 7.5Hz).

Example 25 (A-4) phenyl]-2-chloropropionate 6-acetoxy-2-(4-aminophenoxymethyl) -2,5
, Otsu 8-tetramethylchroman 17.5. ! 9 in a mixed solvent of 130ml of acetone and 30metf of water, and while cooling with water, add 3ml of concentrated hydrochloric acid I! , then sodium nitrite 4
．． Dissolve 3 g in 8.5 ml of water and add dropwise. After further dropping 37.3 ml of ethyl acrylate, the temperature was brought to 40-43°C and 680 mp of cuprous oxide was gradually added. Nitrogen generation ends in about 30 minutes.

Add benzene to the two-layer reaction mixture to extract the organic layer, wash the benzene extract with saturated saline, and sulfuric acid)
Dry with IJum and evaporate the solvent. The obtained dark brown oil was subjected to silica gel column chromatography,
Elute with benzene-cyclohexane (1:1 v/v),
Then, the same solution (2:IV/V) was further eluted with benzene.

The target compound was obtained from the portion eluted with benzene-cyclohexane (2:1 v/v) and benzene.

uf value by silica gel thin layer chromatography = 0
．． 39 (Developing solvent; benzene: ethyl acetate = 20:
1).

N Mn spectrum (δ, CDOρ3) 2 pm 1.23 (3H, t, J=7.5)1z).

1.42 (31-I, s).

Approximately 2 (2H, m).

1.98 (3H, s).

2.04 (3H, s).

2.09 (3H, s).

2', 31 (3H, s).

2.6 (2H, br, t, J==6Hz)
.

3.05 (IH, dd, J=15 and 7.5H
z).

3.31 (IH, dd, J: 15 and 7.5i'l
z).

383 and 3.99 (2H, AB type, J=9Hz)
.

4.18 (2H1q, J-75H2) I4.38 (I
H, t, J=7.5FIz).

6.85 (2H, d, J=91Tz).

7.14 (2H, d, J=911z).

Example 26 (A-4) According to Example 25, 1.74 g of 6-acetoxy-2-(4-aminophenoxymethyl)-7-t-butyl-2-methylchroman, 380Tn9 of sodium nitrite,
The desired compound as a pale yellow oil, prepared from 0.8 ml of concentrated hydrochloric acid, 4.5 g of ethyl acrylate, 65 ml of cuprous oxide, and 17 ml of acetone, has the following physical properties.

'FLf value determined by silica gel thin layer chromatography:
0.55 (developing solvent; benzene: ethyl acetate = 5:
1) NMR spectrum (δ, cDax3): 99m 1.23 (3H, t, J==7.5r(z).

1.31 (9H, s).

1.45 (3H, 8).

1.63-2.20 (2H, m).

2.28 (3H, s).

2.72 (2H, br, t, J=7Hz).

3.08 (I H, dd, J=7.5 and 15
Hz).

3.30 (?H, dcl, J=7.5 and 1
5Hz).

388 and 3.98 (2H, AB type, J = 9H
z) +4.18 (2H, q, J=7.5Hz).

4.37 (IH, t, J=7.5Hz).

6.73 (IH, s).

6.85 (IH, 8).

6.88 (2H, d, J=9Hz).

7.15 (2H, d, J=9Hz).

Example 27 (A-5) Ethyl 3-(4-(6-acetoxy-2,5°7.8
-Tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate 9.611 Thiourea 1.
A mixture of 8 g of sulfolane and 11 ml of sulfolane was added to
Heat at 5-120°C for 80 minutes. Thereafter, 90ml of acetic acid was added to the reaction mixture. Concentrated hydrochloric acid 30ml1. and water 15m/! Add the mixture and heat at 85-90°C for an additional 12 hours. 21 g of sodium hydrogen carbonate is added to the reaction mixture, and after the generation of carbon dioxide gas is completed, the solvent is distilled off. A 10:1 (V/V) mixed solvent of benzene and ethyl acetate was added to the crude product, and a saturated aqueous solution of sodium carbonate: water (1:
1, wash with v/v). Collect the white powder produced,
The product was further washed with water and recrystallized from acetone to obtain the target compound (a).

Melting point: 205-207°C NMR spectrum (δ r dy dmf + D2
0): 99m 1.37 (3H, S).

Approximately 2 (2H, m).

2.02 (3H, S).

2.14 (6H, 8).

(2,3-3,1, solvent absorption).

3.42 (IH, dd, J=15 and 4.5Hz).

4.60 (H(, dd, J: 9 and 4.51 Tz).

6.93 (2H, d, J=911z).

7.23 (2H, d, J=9Hz).

The organic layer obtained by removing the white powder was washed with water, and then
Dry with sodium sulfate and evaporate the solvent. The resulting composition was subjected to silica gel column chromatography, eluted with benzene:ethyl acetate (10:1 v/v), and then the target compound was detected from the portion eluted with benzene:ethyl acetate (10:1.4). (I got bl.

Melting point: 184-186°C NMR spectrum (δ heavy acetone): ppm,
' 1.39 (3H, s).

Approximately 2 (2H, m).

2.02 (3H, S).

2.09 (3H, S).

2.13 (3H, s).

2.63 (2H, br, t, J=61'lz).

3.07 (IH, dd, J=15 and 9H2).

3.41 (IH, dd, J=15 and 4.5Hz)
.

3.97 (2H, AB type, J=9Hz).

4.70 (IH, dd, J=9 and 4.5FIz).

6.90 (2H, d, J=9Hz).

7.21 (2) (, d, J=9Hz).

Example 28 (A-5) Ethyl 31:4-(6-acetoxy-2,5°7.8
-Tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropropione-)9.611 Thiourea1.
A mixture of 89 and sulfolane 11+++l is heated at 120° C. for 35 hours in a nitrogen stream.

Then 100m of ethylene glycol monomethyl ether
1. 70ml/V of 10% hydrochloric acid was added, and the mixture was heated under reflux for 12 hours, and treated and purified in the same manner as in Example 27 to obtain the target compound. The melting point and NMR spectrum were consistent with that in Example 21.

Example 29 (A-5) According to Example 28, ethyl 3-[4-(6-acedoxy7-t-butyl-2-methylchroman-2-1-lmethoxy)phenyl':1-2-chloropropro A mixture of 1.43 g of pionate, 430 mg of thiourea, and 5 ml of sulfolane was heated at 120° C. for 3.5 hours, then 15 ml of ethylene glycol monomethyl ether was added.
The target compound (pale yellow powder) produced by adding 10 ml of 10% hydrochloric acid and heating under reflux for 13 hours has the following physical properties.

Rf value determined by silica gel thin layer chromatography: 0.
31 (developing solvent; benzene:ethyl acetate = 5:1) NMR spectrum (δ, CDCQ3): 99m 1.37 (9H, s).

1.43 (3H, s).

1.63-2.30 (2H, m).

2.67 (2H, br, t, J=7Hz).

3.07 (IH, ad, J: 9 and 15 [1z).

3.45 (IH, dd, J: 4 and 15 Hz).

3.87 and 3.97 (2H, AB type, J=9Hz
).

4.48 (IH, dd, J=4 and 9Hz).

4.62 (IH, br, s, disappeared by addition of heavy water).

6.41 (IH, s).

6.78 (IH, s).

6.88 (2H, d, J=9Hz).

7.15 (2n, d,,y=9Hz).

8.40-8.93 (IH, br, disappeared with addition of heavy water).

Example 30 (H-1) 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione 278 m9 and methyl alcohol 450 μ of sodium borohydride was added to the mixture of 9me and stirred at room temperature for 2 hours. After adding a 1% acetic acid aqueous solution to the reaction mixture, the mixture was neutralized with a potassium carbonate aqueous solution and extracted with ethyl acetate. After washing the ethyl acetate solution with water, it is dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent: hexane: ethyl acetate = 5:3).
The target compound was obtained.

Melting point: 102-118°C NMR spectrum (δ single acetone and heavy water): 9
9m 1.52 (3H, S).

2.01 (3H, s).

2.13 (3H, S).

2.29 (3H, s).

1.9-2.5 (IH, nd).

2.9-3.6 (2H, m).

4.03 (2H, s).

3.9-4.5 (IH, nd).

4.6-5.1 (2H, m).

6.7-7.4 (4H, nd).

Example 31 (H-2) According to the reaction conditions of Example 22, 5-[4-(4゜6-
cyhydroxy-2.5.7.8-tetramethylchroman-2-ylmethoxy)benzylchothiazolidine-2,4
-Dione 1401ng, p-) Luenesulfone M'10
yytq, benzene HJm/! The target compound prepared from 0.5 ml of dimethylformamide has the following physical properties.

Softening point: 173-176℃ NMR spectrum (δ double acetone): 99m 1.50 (3H, s).

2.02 (3H, s).

2.12 (3H, s).

2.18 (3H, s).

3.06 (I H, dd, , J=9Hz and 14Hz).

3.40 (I H, dd, J=4FIz and 1
4Hz).

3.94 (IH, d, J=101'lz).

4.05 (IH, d, J=I GHz).

4.70 (IH, dd, J, = 4 and 9 Hz).

5.75 (IH, d, J=10Hz).

6.72 (IH, d, J=10h).

6.85 (2H, d, J=91(z).

7.19 (2H, d, J = 9Hz).

Example 32 (H-3) According to the reaction conditions of Example 23, 5-(4-(6-hydroxy-2,5,8-tetramethyl-2H-rio),
I 7-2-4-methoxy)benzylchothiazolidine-
120 m9 of 2,4-dione was dissolved in 4 ml of methanol, and the hydrogen pressure was 3-5 in the presence of 40 m9 of 10% palladium on carbon.
Melting point and NMR of target compound obtained by reduction at atmospheric pressure
The spectrum matched that in Example 27.

Reference example 1 t-butylhydroquinone 1oOg, acetic anhydride 130ml
．． and boron trifluoride acetic acid complex salt (40%) 1 kg
The mixture was heated with stirring at 60°C for 2 hours, and then further heated at 90°C for 2 hours. After cooling, the reaction mixture is poured into ice water 31 and extracted with benzene. Add the extract to water,
Wash sequentially with an aqueous IJ carbonate solution and water, dry over anhydrous sodium sulfate, and then evaporate the solvent. The obtained oil was subjected to silica gel column chromatography (eluent;
benzene) to obtain the target compound.

Melting point: 86.5-87.5℃

Claims (1)

[Claims] 1. General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^2 represents a hydrogen atom or a lower alkyl group, R^3 represents a hydrogen atom, an aliphatic lower acyl group, Alicyclic acyl group, aromatic acyl group which may have a substituent, heterocyclic acyl group, aromatic aliphatic acyl group which may have a substituent, lower alkoxycarbonyl group or aralkyloxycarbonyl group and R^4 and R^5 are the same or different and represent a hydrogen atom, a lower alkyl group, or a lower alkoxy group. ] Compounds represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. shows. ] By reacting the compounds represented by the general formula ▲ there are mathematical formulas, chemical formulas, tables, etc. indicates the same meaning. ] A compound represented by is produced, and the compound is reduced and optionally acylated to form the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^3' is the same or different R^ as mentioned above.] Indicates a group having the same meaning as 3, R^1, R^2, R^3, R
^4, R^5 and n have the same meanings as described above. [In the formula, R^1, R^2, R^3, R^4, R ^5 and n have the same meanings as described above. ] This is then reduced to give the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ [In the formula, R^1, R^2, R^3, R^4, R^5 and n indicates the same meaning as described above. ] A compound represented by the following is obtained, the compound is diazotized, and then the general formula CH_2=CH-A' is obtained. [In the formula, A' represents a cyano group, a carboxy group, an alkoxycarbonyl group, or a carbamoyl group. ] There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. for the acrylic acid derivative represented by the acrylic acid derivative and the mailvine arylation reaction ▼ [In the formula, R^1, R^2, R^3, R^4, R^5 and n have the same meanings as described above, X represents a halogen atom, and A represents a group having the same meaning as A' and the formula -COO
M (wherein M represents an equivalent cation)], the resulting compound is reacted with thiourea, and if necessary, further hydrolyzed. There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1, R^2, R^3, R^4, R^5 and n have the same meanings as above, and Y and Z are oxygen atoms. Or represents an imino group. ] A method for producing a thiazolidine derivative represented by 2. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 and R^2 are the same or different and represent a hydrogen atom or a lower alkyl group, R^3 is a hydrogen atom,
Aliphatic lower acyl group, alicyclic acyl group, aromatic acyl group that may have a substituent, heterocyclic acyl group, aromatic aliphatic acyl group that may have a substituent, lower alkoxycarbonyl group or an aralkyloxycarbonyl group, R^4 and R^5 are the same or different and represent a hydrogen atom, a lower alkyl group or a lower alkoxy group, and n represents an integer of 1 to 3. ] General formula obtained by reducing the compound represented by and further acylating if necessary ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^3' is the same or different as the above-mentioned R^3 Indicates a group expressing the meaning, R^1, R^2, R^3, R
^4, R^5 and n have the same meanings as described above. ] When a compound represented by the following is subjected to an elimination reaction, the general formula ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ [In the formula, R^1, R^2, R^3, R^4, R^5 and n indicates the same meaning as above. ] There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by reducing the resulting compound with the compound represented by ▼ [In the formula, R^1, R^2, R^3, R^4 , R^5 and n have the same meanings as described above. ] A method for producing a thiazolidine derivative represented by