JPH0645619B2 - Method for producing thiazolidine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has blood lipid and glucose metabolism improving action, that is, blood lipid peroxidation lowering action, blood triglyceride lowering action, blood cholesterol lowering action and low sugar lowering action,
It also relates to the production of novel thiazolidine derivatives with extremely low toxicity. More specifically, the present invention has the general formula Wherein (1) the ^{R 1} and ^{R 2} are the same or different connexion hydrogen atom or a lower alkyl group, ^{R 3} and described below R
^{3 'is} a hydrogen atom, an aliphatic lower acyl group, an alicyclic acyl group, optionally substituted aromatic acyl group, a heterocyclic acyl group, an aromatic alicyclic have a substituent A carbamoyl group which may be substituted with an acyl group, a lower alkoxycarbonyl group, an aralkyloxycarbonyl group, or a lower alkyl group, R ⁴ and R ⁴ are the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, n is an integer of 1 to 3, W is a methylene group, a carbonyl group or a formula And Y and Z represent an oxygen atom or an imino group. ] A method for producing a thiazolidine derivative represented by the above formula, and a method for converting a substituent of the thiazolidine represented by the formula (1) from a carbonyl group to a methylene group.

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

Method A Method A is a method which has already been described in detail by the present inventors in JP-A-60-51189 (abbreviated as the preceding item 1) and has a general formula
In (1) , it is advantageously used for producing a compound in which W is a methylene group. According to this method, as shown below, the compound (3) is a target compound. Be led to. (A-1 → A-5) In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n have the same meanings as described above, m is an integer of 0 to 2 and X is
Is a halogen atom such as chlorine or bromine, especially a bromine atom, and A is an alkoxycarbonyl group such as a cyano group, a carboxy group, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, particularly a butoxycarbonyl group, a carbamoyl group or a formula —COOM ( In the formula, M represents an equivalent cation), Represents a thiazolidine derivative in which W is a methylene group, R
₁₀ is shown later.

A-1 This step is a reduction step using a metal hydride such as lithium aluminum hydride and bitride (sodium bis (2-methoxyethoxy) aluminum hydride).

A-2 This step is a step of converting chroman alcohols (4) into chromanes (5) having a nitro group. It is preferable to protect the phenolic hydroxyl group prior to the reaction, and examples of the hydroxyl-protecting group R ₁₀ include methoxymethyl and 2-
Alkoxyalkyl groups such as tetrahydropyranyl and the like are preferred. Chroman alcohols having a protected phenolic hydroxyl group can be isolated, but they can be isolated by the general formula (In the formula, X has the same meaning as described above ), and leads to a chroman (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 amino compound (5) . In the reduction reaction, the protecting group R ₁₀ for the phenolic hydroxyl group of the nitro compound (5) may be used as it is, but may be deprotected, and further another group, for example, an acyl group such as an acetyl group or a benzoyl group. May be changed to, and it is preferable to change to an acyl group. When carrying out deprotection of compound (5) , the deprotection step is achieved by hydrolyzing (5) in the presence of a low concentration of acid. When the protecting group of the compound (5) is changed to an acyl group or the like, the acylation is carried out by further adding a compound deprotected by the above hydrolysis to an acid halide such as acetyl chloride or benzoyl chloride or an acid such as acetic anhydride. This is achieved by treatment with an acylating agent represented by anhydrides. The reduction reaction from the nitro form (6) to the amino form (6) 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 In this step, cuprous oxide, cupric oxide such as cupric oxide, cuprous chloride, cupric chloride, cuprous bromide, cupric bromide or hydrates thereof The aromatic amino compound (6) is diazotized in the presence of a copper ion such as
₂ = CH-A ', an acrylic acid derivative (in the formula,
A'represents a cyano group, a carboxy group, an alkoxycarbonyl group or a carbamoyl group. ) With a Melbine arylation reaction to give a precursor of the object compound (1) of the present invention, α-halogen carboxylic acid derivatives
Is converted to (7) .

A-5 In this step, a thiazolidine derivative in which Z is an imino derivative by reacting compound (7) with thiourea Or, if necessary, a hydrolysis reaction is carried out, and a thiazolidine derivative in which Y and Z are oxygen atoms And R ³ is a hydrogen atom Can also be

Method B Method B is advantageously used for producing a compound of the general formula (1) in which W is a methylene group and n is 2. Among chroman alcohols (4) , particularly those in which n is 2, (8) are, for example, Journal of American
Oil Chemistry Society 51 , 200 (1974)
Hydroxys (9) by the method described in Thus, as described above, it can be manufactured through multiple steps, but it can be manufactured in one step according to the method disclosed in JP-A-58-201775, and can be manufactured by the steps A-2 to A-5. The target compound can be produced. R ¹ , R ² , R
³ , R ⁴ and R ⁵ have the same meanings as described above.

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

This method is based on the Journal of Medicinal Chemistry.
Vol. 18 , p. 934 (1975), wherein R ¹ ′ at the 2-position of the chroman ring (R ¹ ′ is the above-mentioned R ¹
The hydrogen atom is excluded from the definition of. Can be advantageously used to introduce a).

According to this method, as shown below, the compound (9) is the target compound. Be led to.

(C-1 → C-11) In the above formula, R ¹ ′, R ² , R ⁴ , R ⁵ , and R ₁₀ have the same meanings as described above, B ₁ is a carboxylic acid protecting group,
Examples thereof include an alkyl group, an alkenyl group, an alkynyl group, an aralkyl group and an optionally substituted phenyl group, preferably a lower alkyl group, and particularly a hydrogen atom when protection is not required.

C-1 to C-4 The respective steps are essentially the same as the method described in the above literature.

C-5 Step C-5 is a step for protecting the phenolic hydroxyl group, which is carried out as necessary, but it is preferable to protect the phenolic hydroxyl group prior to the step C-6. When protecting the hydroxyl group, as the protecting group R ₁₀ , a usual phenolic hydroxyl protecting group, for example, an alkoxyalkyl group such as methoxymethyl or 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 or calcium hydride, or sodium methoxide, sodium ethoxide or 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 dimethyl sulfoxide, and sulfones such as sulfolane. Compound (1
The ratio of 2) to the alkylating agent is not particularly limited,
It is advantageous to use a slight excess of the alkylating agent relative to (12) . Preferably, the alkylating agent is 1 to 10 mol per 1 mol of the compound (12) . Reaction temperature,
The reaction conditions such as reaction time will differ depending on the starting materials used, solvent, etc., but usually the reaction is 0 to 50 ° C., preferably 10-
It is carried out at 25 ° C for several minutes to several tens of minutes. 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.

C-6 The C-6 step is a step of producing a chromancarboxylic acid derivative (14) having a protected hydroxyl group at the 6-position of the chroma ring and R ¹ ′ at the 2-position of the same ring, if desired. Chromancarboxylic acid having a hydroxyl group protected at the 6-position (1
3) is treated with a base in an inert solvent to generate a carbanion in the reaction solution, and then the general formula R ¹ ′ -X ′ (in the formula, R ¹ ′ has the same meaning as described above, X ′ Is a base, a halogen atom such as bromine or iodine, or a sulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy and p-toluenesulfonyloxy). To be achieved.
Examples of the base used include methyllithium, n
-Butyllithium, t-butyllithium, organolithium compounds such as phenyllithium: lithium dialkylamides such as lithium diisopropylamide, lithium dicyclohexylamide, lithium isopropylcyclohexylamide, or thylium hydride,
Examples thereof include alkali metal hydrides such as sodium hydride and potassium hydride, and preferred are organic lithium compounds or lithium dialkylamides.

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

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

The steps C-7 to C-11 correspond to the steps A-1 to A-5, respectively.
Target compound in which R ¹ is an alkyl group Is manufactured.

If desired, by using (13) and directly carrying out a reaction according to C-7 to C-11 without going through the C-6 step, the target compound in which R ¹ is a hydrogen atom is obtained. Can be manufactured.

Method D This method is a method which has already been described in detail by the present inventors in JP-A-61-36284 (abbreviated as the previous item 2) and has a general formula
In (1) , it is advantageously used for producing a compound in which W is a carbonyl group. According to this method, as shown below, the compound (2) is a target compound, Be led to. (D-1 → D-4) In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , A, X and n have the same meanings as described above, Represents a thiazolidine derivative in which W is a carbonyl group.

D-1 In this step, acetophenone derivatives (2) were converted to nitro form
By reacting (15) with pyrrolidine, piperidine, or an organic base such as morpholine, 4-oxochroman derivatives (16) having a nitrophenoxy group are produced.

Each of D-2, D-3, and D-4 processes corresponds to A-3, A-4, and A-5 processes, respectively, and as described above, the target compound in which W is a carbonyl group, Is manufactured.

Method E The method E is represented by the general formula (1) in which W is a carbonyl group,
It is also advantageously used to prepare compounds having the substituent R ¹ ′ at the 2-position of the chroman ring. According to this method, as shown below, the compound (11) is introduced into the intermediate (25) . (E-1 → E-7) Chromonecarboxylic acid obtained in the C-3 step Reducing (E-1) only the double bond formed by the carbon atoms at the 2- and 3-positions under milder conditions than those used in the step ( C-4); and E-2 to E
Each step of -7; In the formula, R ¹ ′, R
² , R ⁴ , R ⁵ , R ₁₀ and B ₁ have the same meanings as described above, and B ₂ represents a protected carbonyl group.

Each step will be described in detail below.

Step E-1 Step E-1 is a step of obtaining 4-oxochromancarboxylic acids (19) from chromonecarboxylic acids (11) .
Catalytic reduction is used as the reduction method. The catalyst used for catalytic reduction is palladium-carbon, Raney-Nickel,
Platinum oxide and the like can be mentioned, but palladium-carbon is preferable. 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 used and the solvent, but usually the temperature to 50
C., preferably room temperature to 40.degree. C., for a few minutes to a few days, preferably about 30 minutes to about 20 hours.

E-2 The E-2 step is for 4-oxochromancarboxylic acids (19)
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 (20) [wherein R ² , R ⁴ , R ⁵ , and
B ₁ has the same meaning as described above, and B ₂ is the formula −B ₃ −B ₄ −B ₃
-, B ₃ represents an oxygen atom or a sulfur atom, preferably a sulfur atom, and B ₄ represents, for example, the formula — (CH ₂ ) ₂ —, the formula — (C
H ₂ ) _3- , 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 the formula − (CH ₂ ) ₃ −. ] Is usually manufactured by
-Oxochromancarboxylic acids (19) and H-such as ethylene glycol, 1,3-propanediol, 1,2-ethanediol, 1,3-propanedithiol or cis-2-butene-1,4-diol B ₃ -B ₄ -B ₃ -H (wherein, B
₃ and B ₄ have the same meaning as described above. A), preferably 1,3-propanedithiol, is dehydrated in the presence or absence of a catalyst. As the catalyst, boron trifluoride, its ether complex salt, its acetic acid complex salt, Lewis acid such as aluminum chloride; or inorganic acids such as hydrochloric acid and sulfuric acid;
Organic acids such as acetic acid, succinic acid, fumaric acid, maleic acid, paratoluenesulfonic acid, or methanesulfonic acid can be mentioned, but 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, benzene, aromatic hydrocarbons such as xylene, halogenated hydrocarbons such as chloroform and dichloromethane are used as the solvent.
Preferable examples include halogenated hydrocarbons such as chloroform. Compound _{(19) H-B 3 -B} 4 -
Although ₃ ratio of the -H is not particularly limited, compound (19) in slight excess from equimolar to H-B ₃ -B ₄ - ₃ it is preferable to use -H. Preferably compound (19) with respect to 1 mol, H-B ₃ -B ₄ - a ₃ -H1 to 2 moles. Compound
The ratio of (19) to the catalyst is not particularly limited, but the compound
(19) The catalyst is 1 to 4 mol per 1 mol. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials used and the type of solvent used, but they are generally 0 ° C to 100 ° C, preferably 10 ° to 40 ° C, and several minutes to several days, preferably 1 hour to 30 hours.

E-3 Step E-3 is a step of protecting the phenolic hydroxyl group at the 6-position of the oxochromancarboxylic acid (20) in which the 4-position of the chroman ring is protected, if desired.
It is preferable to carry out the protection prior to the alkylation reaction at the 2-position of the chroman ring in the step.

As the hydroxyl-protecting group R ₁₀ , a usual phenolic hydroxyl-protecting group, for example, an optionally substituted alkyl group such as methoxymethyl or 2-tetrahydropyranyl, or an optionally substituted benzine group, Further, an acyl group such as acetyl and benzoyl can be mentioned, but an alkoxyalkyl group is preferable. The reaction for introducing a protecting group is carried out, for example, with alkali hydrides or alkaline earth metals such as sodium hydride, potassium hydride, calcium hydride, sodium methoxyside, sodium ethoxyside, potassium tertiary butoxide. This is accomplished by using an alkoxyalkylating agent such as chloromethyl methyl ether or an alkylating agent such as benzyl halide in the presence of bases 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 dimethyl sulfoxide, and sulfones such as sulfolane. The ratio of the compound (20) to the alkylating agent is not particularly limited, but it is preferable to use the alkylating agent in a molar excess over an equimolar amount with respect to (20) , preferably (20) 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, solvent, etc. used, but usually the reaction is 0 to 50 ° C.
It takes several minutes to several hours. The chromancarboxylic acids (21) thus protected can be isolated, but can also be used in the E-4 step without isolation.

E-4 Step E-4 is, if desired, a chromane carboxylic acid having a hydroxyl group protected at the 6-position of the chroman ring, a carbonyl group protected at the 4-position of the same ring, and a chromancarboxylic acid having R ¹ ′ at the 2-position of the same ring (22 In the process of producing ) , a hydroxyl group protected at the 6-position of the chroman ring,
Chroman carboxylic acids (21) 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 ′ is a halogen atom such as chlorine, bromine, iodine or methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy. And a compound having a sulfonyloxy group such as) is reacted.
Examples of the base used include methyllithium, n
An organolithium compound such as -butyllithium, t-butyllithium, phenyllithium; a lithium dialkylamide such as lithium diisopropylamide, lithium dicyclohexylamide, lithium isopropylcyclohexylamide; or lithium hydride
Alkali metal hydrides such as sodium hydride, potassium hydride and the like can be mentioned, 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, but ethers such as ether, tetrahydrofuran and dioxane are preferably used.

The reaction temperature is −78 ° C. to room temperature for the generation of the anion in the first stage, and 0 ° C. to 60 ° C. for the reaction between the anion in the second stage and the compound R ¹ ′ -X ′, and the time required for the reaction is 30 minutes to 2 hours, followed by 1 hour to 24 hours
It's time.

If desired, chromancarboxylic acids (21) in which R ¹ is a hydrogen atom are used, and the reduction reaction according to the E-5 step is directly performed without passing through the E-4 step, and each of the following respective reactions. By carrying out the reaction, the target compound in which R ¹ is a hydrogen atom Can be manufactured.

E-5 E-5 step is chroman-2-carboxylic acid(22)
The corresponding alcohols according to step A-1(2
3)And the reducing agent is, for example,
Lithium Aluminium Hydride, Bitride (Sodium
Dium bis [2-methoxyethoxy] aluminum
 Hydrides) such as
Be done. Examples of the solvent used in the reduction reaction include:
Diethyl ether, tetrahydrofuran, ethylene glycol
Ethers such as kohl dimethyl ether, benze
Aromatic hydrocarbons such as ethylene, toluene, xylene,
Xane, heptane, cyclohexane, petroleum ether,
Aliphatic hydrocarbons such as groin, ethylcyclohexane
And the like.

The ratio of the compound (22) to the reducing agent is not particularly limited, but it is preferable to use a slight excess of the reducing agent with respect to the compound (22) . Preferably, 1 mol per 1 mol of compound (22)
~ 2 moles. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials used, solvent, etc.
It is about 10 minutes to about 20 hours at ° to 120 ° C.

E-6 The E-6 step is the alcohol (2) obtained in the E-5 step.
Based on 3) Is a step of introducing. This step is carried out by using a compound (23) , usually a base, for example, an alkali hydride or an alkaline earth metal such as sodium hydride or calcium hydride,
In addition, an alkali metal alcoholate such as sodium methoxide, sodium ethoxide, and potassium tertiary butoxide is preferably reacted with sodium hydride or sodium ethoxide to give a compound.
(23) is the corresponding alkoxide, and the general formula This is achieved by reacting a compound having the formula (wherein X has the same meaning as defined above).

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 (23) to the base is not particularly limited, but it is preferable to use a slight excess of the base with respect to the compound (23) , preferably 1 to 2 bases per 1 mol of the compound (23). It is a mole.
Compound (23) and compound The ratio of and is not particularly limited, but an excess amount of the compound with respect to the compound (23) Is preferably used, and preferably (23) per 1 mol, It is 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 (24) having a carbonyl group protected at the 4-position of the chroman ring obtained in this step is D-2, D-
3, a target compound through a reduction reaction represented by D-4, a mail vine arylation, and a reaction with thiourea However, the deprotection reaction at the 4-position of the chroman ring may be carried out at any of the above steps. For example, one of the preferable methods is the step shown in E-7. .

E-7 Step E-7 is a step of deprotecting the nitro compound (24) having a hydroxyl group protected at the 6-position of the chroman ring and a carbonyl group protected at the 4-position, if desired. In this step, the deprotection reaction at the 4-position is usually carried out, but the deprotection at the 6-position can be achieved at the same time by setting reaction conditions that are rather radical.

The deprotecting agent is not particularly limited, but a conventional deprotecting agent, for example, a protic acid such as hydrochloric acid or sulfuric acid; boron trifluoride, an ether complex salt thereof, an acetic acid complex salt thereof, a Lewis acid such as aluminum chloride; Especially when B ₃ is a sulfur atom,
Heavy metal salts, heavy metal oxides or heavy metal peroxides; or mixtures of two or three of these; examples of heavy metal ions are silver, cadmium, divalent mercury, divalent copper, trivalent thallium. Examples of the counter ion of heavy metal ions include halogen ions such as chlorine, bromine and iodine, and peroxide ions such as nitrate ion and perchlorate ion; and other sulfuryl halides such as iodine and sulfuryl chloride. Examples thereof include N-haloimides such as N-chlorosuccinimide and N-bromosuccinimide, preferably mercuric chloride or mercury 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, ethers such as tetrahydrofuran and dioxane. , Organic acids such as acetic acid,
Examples thereof include nitriles such as acetonitrile, water, and a mixed solvent thereof.

The ratio of the compound (24) to the deprotecting agent is not particularly limited,
Usually (24) 1 to 10 moles of a deprotecting agent,
It is preferably 1 to 4 mol. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials and solvent used, but are usually room temperature to 100 ° C, preferably 40 to 80 ° C.
It is several minutes to several hours, preferably 0.5 to 4 hours.

Thereafter, using the obtained compound (25) , the target compound is obtained by sequentially using a method according to the method of Step D-2 or below. Manufacturing is achieved.

Method F Method F is a target compound in which W is a methylene group, Is advantageously used to prepare the compound (16) shown in the description of Method D in which W is a carbonyl group.

According to this method, as shown below, the compound (16) is introduced into the intermediate (6) . (F-1 → F-5) In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and n have the same meanings as described above, and ▲ R ³ _a ▼ 'represents R ³ excluding a hydrogen atom. .

F-1 In the F-1 step, the 4-oxochroman compound (16) having a nitro group is converted to the corresponding 4-hydroxy compound (2
This is a step of reducing to 6) . Examples of the reducing agent include reducing agents such as sodium borohydride and k-selectride, and the reducing reaction is preferably achieved with sodium borohydride.

The reaction of compound (16) 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 (16) to sodium borohydride used is not particularly limited,
It is advisable to use an excess of sodium borohydride with respect to (16) . It is preferably 1 to 20 mol per 1 mol of the compound (16) . The reaction conditions such as reaction temperature and reaction time vary depending on the starting materials, solvent and the like used, but the reaction is usually at 0 to 100 ° C. for 1 to 20 hours.

F-2 In the F-2 step, the hydroxy derivative (26) can be used, if desired.
Is a step of acylating.

The compound (26) can be converted to the desired acyl compound (28) by reacting with an acid halide or with an acylating agent such as an acid anhydride.

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

The ratio of the compound (26) 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 (26) . Preferably compound (26)
The amount of the acylating agent is 1 to 10 mol per 1 mol. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials used and the type of solvent used, but they are generally 0 to 100 ° C. and several minutes to about 20 hours.

F-3 Step F-3 is a step of producing 2H-chromenes (27) by removing water from the 4-hydroxychroman compound (26) having a nitri group.

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

A solvent may not be used in the elimination reaction, but when a solvent is used, alcohols such as methanol, ethanol and isopropanol, acetone, methyl,
Ketones such as ethyl ketone, ethers, tetrahydrofuran, ethers such as dioxane, benzene,
Aromatic hydrocarbons such as 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, pyridine and triethylamine. Organic bases, amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, sulfonic acids such as sulfolane, and water, preferably aromatic hydrocarbons such as benzene. And organic acids such as acetic acid. When a dehydrating agent or a dehydrating catalyst is used, the ratio of the compound (26) to the dehydrating agent or the dehydrating catalyst is not particularly limited, but is usually a compound
(26) The amount of the dehydrating agent or dehydrating catalyst is 0.
The amount is 01 to 10 mol, preferably 0.1 to 3 mol. The reaction conditions such as reaction temperature and reaction time will differ depending on the starting materials used and the type of solvent used, but they are generally 0 to 100 ° C. and several minutes to about 20 hours.

F-4 The F-4 step is performed by converting the 4-acyloxychroman compound (28) having a nitro group into the compound ▲ R ³ _a ▼ 'OH (▲ R
³ _a ▼ ′ has the same meaning as described above. ) Is released to produce 2H-chromenes (27) .

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

As 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 paratoluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, inorganic salts such as ammonium chloride and calcium chloride, Examples thereof include organic bases such as pyridine and triethylamine, silica gel, alumina, and the like, with preference given to organic acids such as acetic acid and sulfonic acids such as paratoluenesulfonic acid.

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

When a deoxidizing agent or deoxidizing catalyst is used, the compound (2
The ratio of 8) to the deoxidizing agent or the deoxidizing catalyst is not particularly limited, but usually 0.01 mol to 10 mol of the deoxidizing agent or the deoxidizing catalyst, preferably 1 mol of the compound (28). Is
It is 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 (6) having an amino group by simultaneously reducing the nitro group and the carbon-carbon double bond of 7) .

A catalytic reduction method is preferably used for the reduction reaction. Examples of the catalyst used for catalytic reduction include palladium-carbon, Raney-Nitzkel, platinum oxide and the like, but palladium-carbon is preferable. The hydrogen pressure is 1 atm to 100 atm, preferably 1 atm to 6 atm. Examples of the solvent include alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, organic acids such as acetic acid, water, and a mixture of these. Reaction temperature,
While the reaction time varies depending on the starting materials and solvent used, it is generally several minutes to about 20 hours at room temperature to 50 ° C.

After that, the production of α-halogenocarboxylic acid derivatives (7) is achieved by the step A-4 using the obtained compound (6) .

In addition, F-1, F-2, F-3, F-4, F-5, A-
4 and / or the final step for producing the desired thiazolidine derivative is sequentially carried out, if desired, with the intermediate (2
6) , (27) , (28) , (6) , and / or
(7) can be carried out without isolation.

Further, for example, the steps shown by Method F are not limited to the order shown. That is, for example, the nitro group having the compound (16) in which the 4-position of the chroman ring is a carbonyl group is first reduced, then the 4-position carbonyl group is reduced, and further dehydrated to 2H-chromene, followed by the reduction reaction. Performing the amino compound (6) is the same as in the F method.

G method G method is similar to F method and can be expressed by the general formula
(1)In which W is a methylene group,
From a compound in which the 4-position of the ring is a carbonyl group.
Can be used for That is, D method, E method, and
And deprotection of the protecting group for the hydroxyl group at the 6-position of the chroman ring described in Method A.
Protection reaction, the same as that produced by the acylation reaction of the hydroxyl group,
B₂Is the formula -S- (CH₂)_p-S-, (In the formula, p represents 2,3,4
You Compound having(29)Or(31)Ranet
-NickelChromane 4 when catalytically reduced by a nickel catalyst such as
Compounds where the position is methylene(30)Or(32)
Can be obtained respectively.

The hydrogen pressure is 1 atm to 100 atm, preferably 1 atm to 6 atm. Examples of the solvent include alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, organic acids such as acetic acid, water, and a mixture 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 several minutes to about 20 hours.

Method H is a thiazolidine derivative in which W is a carbonyl group in the general formula (1) , particularly a compound (33) in which Y and Z are both oxygen atoms, and a compound in which W is a methylene group.
It is converted into (36) .

Where R ¹ , R ² , R ³ , R ³ ′, R ⁴ , R ⁵ and n
Has the same meaning as described above.

H-1 In this step, W, which is one of the target compounds, is a carbonyl group,
A thiazolidine derivative in which both Y and Z are oxygen atoms (3
3) is reduced with a reducing agent such as sodium borohydride or K-selectride, especially sodium borohydride, and further reacted with an acylating agent if necessary, and W is represented by the formula (In the formula, R ³ ′ has the same meaning as described above), and the thiazolidine derivative (34) can be converted into the details, which are the same as those described in 2 above.

H-2 In this step, after H-1 is followed by —OR ³ ′ at the 4-position of the chroman ring.
(In the formula, R ³ ′ has the same meaning as described above) is eliminated to obtain a thiazolidine derivative (35) in which the chroman ring 3 and 4 positions are carbon-carbon double bonds. For details, see F-3 and / or F-4 in the present invention.
It is similar to the process.

H-3 This step is to reduce the double bond after H-2 and is one of the target compounds according to this step.
In the formula (1) , a thiazolidine derivative (36) in which W is a methylene group; Y and Z are both oxygen atoms is produced. The details are described in the F-5 step (provided that F
In step -5, the reduction reaction of the nitro group is similarly performed. ).

The thiazolidine derivative according to the present invention in which R ³ and / or R ³ ′ is a hydrogen atom can be converted to the corresponding ester by a conventional method.

The method for producing the thiazolidine derivative (1) , that is, the B, C, E, F, G, and H methods for explaining the present invention,
Preferred are methods C, E, F and H; more preferred are methods C, F and H; particularly preferred are methods F and H.

The most preferable compound in the present invention, that is, in the formula (1), R ¹ , R ² , R ⁴ and R ⁵ represent a methyl group, and R ³
Represents a hydrogen atom, W represents a methylene group, Y and Z
When producing a compound in which is an oxygen atom and n is 1, a production method in which the following steps are sequentially performed is preferable.

That is, the compound having the formula (2) is reacted with the compound having the formula (15) to produce the compound having the formula (16) (step D-1), and then the obtained compound is reduced to give the formula ( 26) is produced (step F-1), then the obtained compound is subjected to a dehydration reaction to produce a compound having the formula (27) (step F-3), and then the obtained compound is obtained. Reduction to produce a compound having formula (6) (F-5
Step), then diazotizing the obtained compound, and further represented by the general formula CH ₂ ═CH—A (wherein A represents a carboxy group or an alkoxycarbonyl group, particularly a butoxycarbonyl group). To produce a compound having the formula (7) by subjecting it to a Meylbaine arylation reaction (step A-4), and then reacting the obtained compound with thiourea, and optionally by hydrolysis. A method for producing a compound having (1).

According to this method, not only the process is shortened and the yield is improved,
The use of harmful, toxic, and odorous substances, the minimization of industrial waste, and other purposes are notable, and as a result, the contribution to the conservation of the so-called global environment such as the living environment and working environment is noted.

In the compound (1) , the carbon atom at the 2-position of the chroman ring and the 5-position of the azoline ring are asymmetric carbon atoms,
Each isomer based on them is also included in the formula (1) .

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

(Abbreviation: For example, 1-Me.butyl is 1-methylbutyl
Indicates. ) Hereinafter, the present invention will be described more specifically with reference to Examples and Reference Examples.

The abbreviations for NMR spectra, nd, overlap with other signals or signals of solvents and the like, indicating that discrimination is impossible.

Example 1 (C-4) Ethyl 6-hydroxy-5,7,8-trimethylchroman-2-carboxylate Ethyl 6-hydroxy-5,7,8-trimethylchromone-2-carboxylate 14 g was dissolved in 320 m of acetic acid. , 1
Hydrogen pressure 3 atm, 60-
It was catalytically reduced at 65 ° C. for 1 hour. The catalyst was separated and the solution was poured into water to deposit white crystals. The melting point of this target product was 108 to 109 ° C.

NMR spectrum (δ _ppm , CDC ₃ ): 1.28 (3H, t, J, = 7Hz), 2.07 (3H, s), 2.17 (6H, s), 1.9 to 2.3 (2H, nd), 2.65 (2H, br) .t, J = 7Hz), 4.22 (2H, q, J = 7Hz), 4.1 to 4.3 (1H, nd), 4.60 (1H, dd, J = 7 and 4Hz).

Example 2 (C-5) Ethyl 6-methoxymethoxy-5,7,8-trimethylchroman-2-carboxylate Ethyl 6-hydroxy-5,7,8-trimethylchroman-2-carboxylate 14.3 g, dimethylformamide
To a 130 m mixture, under nitrogen flow, 3 g of 55% oily sodium hydride (wash twice with cyclohexane) was added little by little at 5-10 ° C. Stir at room temperature for 1 hour, then 3-5
After ice-cooling to ℃, 5.6 g of chloromethyl methyl ether is 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 evaporated 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 = 0.41 (developing solvent; benzene: ethyl acetate = 20: 1) NMR spectrum (δ _ppm , CDC ₃ ): 1.27 (3H, t, J = 7Hz), 2.0-2.4 (2H , nd), 2.15 (3H, s), 2.16 (3H, s), 2.2 (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).

Example 3 (C-6) Ethyl 2-isobutyl-6-methoxymethoxy-5,7,
8-Trimethylchroman-2-carboxylate Diisopropylamine 4.6 g tetrahydrofuran 100 m
To the solution was added 25m of a hexane solution of n-butyllithium (1.62mmo / m) at -20 to -10 ° C and stirred at -5 ° C for 20 minutes, then cooled to -70 to -60 ° C and ethyl 6-methoxymethoxy-. A 10 m solution of tetrahydrofuran containing 2 g of 5,7,8-trimethylchroman-2-carboxylate was added dropwise, and the mixture was stirred at the same temperature for 2 hours. 10 g of isobutyl bromide was added dropwise, and the mixture was left at room temperature overnight, and then heated at 40 ° C for 4 hours. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added, the organic layer was separated, 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; hexane: ethyl acetate = 7: 1) to obtain the desired product.

Rf value of silica gel thin layer chromatography = 0.59 (developing solvent; hexane: ethyl acetate: toluene = 3: 1: 1) NMR spectrum (δ _ppm , CDC ₃ ): 0.9 to 1.3 (9H, nd), 1.4 to 2.7 (7H, nd), 2.10 (3H, s), 2.16 (3H, s), 2.20 (3H, s), 3.60 (3H, s), 4.12 (2H, q, J = 7Hz), 4.86 (2H, s) ).

Example 4 (E-1) Ethyl 6-hydroxy-5,7,8-trimethylchromone-2-carboxylate Ethyl 6-hydroxy-5,7,8-trimethyl-4-oxochroman-2-carboxylate 12 g was added to dimethyl. Formamide 250m, 10% palladium on carbon 16g
Under a hydrogen pressure of 5 atm at 50 to 60 ° C. for 7 hours. The catalyst was removed, the liquid was poured into a large amount of water, and the precipitated crystals were collected. The obtained crystal was recrystallized from ethyl acetate to obtain the target compound.

Melting point: 120-121 ° C NMR spectrum (δ _ppm , CDC 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), extract the solution containing the above target compound with ethyl acetate,
The extract is dried over anhydrous sodium sulfate, then the solvent is distilled off,
The residue is subjected to silica gel column chromatography (eluent;
Hexane: ethyl acetate = 1: 1), and the target compound from the first fraction and ethyl 4,6-dihydroxy-5,7,8-trimethylchroman-2-carboxylate from the second fraction. Obtained.

Melting point: 138-144 ° C.

Example 5 (E-2) Ethyl Spiro [6-hydroxy-5,7,8-toymethylchroman-4,2 '-[1,3] dithiane] -2-carboxylate Ethyl 6-hydroxy-5,7 1,8-Trimethyl-4-oxochroman-2-carboxylate 16.6g, 1,3-propanedithiol 9.7g in a 500m solution of chloroform under ice-cooling Boron trifluoride acetic acid complex salt (boron trifluoride 40%) 20
m was added dropwise 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.

Mp: 186-188 ° C. NMR spectrum _{(δ ppm, CDC 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).

Example 6 (E-3) Ethylspiro [6-methoxymethoxy-5,7,8-trimethylchroman-4,2 '-[1.3] dithiane] -2-carboxylate Ethylspiro [6-hydroxy-5,7 A mixture of 6.6 g of 8,8-trimethylchroman-4,2 ′-[1,3] dithian] -2-carboxylate, 100 m of dimethylformamide and 1 g of 55% oily sodium hydride was sonicated at room temperature for 1 hour. Then, 3 g of chloromethyl methyl ether was added under ice cooling, and the mixture was left in a greenhouse 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).
And the target compound was obtained.

Rf value of silica gel thin layer chromatography = 0.21 (developing solvent; hexane: ethyl acetate = 5: 1) NMR spectrum (δ _ppm , CDC 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).

Example 7 (E-4 and E-5) Spiro [2-isobutyl-6-methoxymethoxy-5,7,
8-Trimethylchroman-4,2 '-[1,3] dithiane]-
2-isomethanol diisopropylamine 3g tetrahydrofuran 90m
15m of hexane solution of n-butyllithium (butyllithium 1.62mmo / m) at -60 ℃ to -50 ℃ in liquid
Was dropped and the mixture was left at room temperature for 20 minutes. Ethyl at -60 ° C
Add 4.8 g of spiro [6-methoxymethoxy-5,7,8-trimethylchroman-4,2 '-[1,3] dithiane] -2-carboxylate, stir for 10 minutes, and then add isobutyl bromide 4.1.
g was added and the mixture was stirred for 30 minutes, then stirred at room temperature for 1.5 hours, further added with 3 g of isobutyl bromide and 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, the organic layer was separated, washed with water and then 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 = 5: 1) to obtain the target compound.

Rf value of silica gel thin layer chromatography = 0.16 (developing solvent; hexane: ethyl acetate = 5: 1) NMR spectrum (δ _ppm , CDC ₃ ): 1.03 (3H, d, J = 6Hz), 1.04 (3H, d , J = 6Hz), 1.70 (2H, d, J = 6Hz), 1.8−2.3 (3H, nd), 2.08 (3H, s) 2.20 (3H, s), 2.3−3.0 (4H, nd), 2.91 ( 3H, s), 3.05-3.95 (5H, nd), 3.62 (3H, s), 4.88 (2H, s).

Example 8 (E-6) Spiro [2-isobutyl-6-methoxymethoxy-5,7,
8-Trimethyl-2- (4-nitrophenoxymethyl)
Chroman-4,2 '-[1,3] dithiane] 55% oily sodium hydride 0.6 g and tetrahydrofuran 2
4m of ethanol was added to the mixture of 0m, and further,
Spiro [2-isobutyl-6-methoxymethoxy-5,7,
8-Trimethylchroman-4,2 '-[1,3] dithiane]-
2-ylmethanol 3.2 g tetrahydrofuran 20 m
The solution was added. After the solvent was distilled off under reduced pressure to dryness, 30 m of dimethylformamide was added, and the mixture was heated at 40 ° C. for 1 hour under reduced pressure. Add 10g of p-nitrochlorobenzene, 50 ℃
Heated for 2 hours.

Water was added to the reaction mixture, extraction was performed with benzene, 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 Lysica gel column chromatography (eluent; hexane: acetic acid = 6: 1) to obtain the target compound.

Rf value of silica gel thin layer chromatography = 0.54 (developing solvent; hexane: ethyl acetate = 2: 1) NMR spectrum (δ _ppm , CDC ₃ ): 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, s), 3.92 (1H, d, J = 4.5Hz), 4.50 (1H, d, J = 4.5Hz), 4.90 (2H, s), 6.90 (2H, d, J = 4.5Hz), 8.17 (2H, d, J = 4.5Hz).

Example 9 (E-7) 2-Isobutyl-6-methoxymethoxy-5,7,8-trimethyl-2- (4-nitrophenoxymethyl) -4-oxochroman (1) and 2-isobutyl-6- Hydroxy-5,7,8-trimethyl-2- (4-nitrophenoxymethyl) -4-oxochroman (2) spiro [2-isobutyl-6-methoxymethoxy-5,7,
8-Trimethyl-2- (4-nitrophenoxymethyl)
A mixture of 3.3 g of chroman-4,2 '-[1,3] dithiane], 4 g of mercuric chloride, 1.4 g of mercuric oxide, and 30 m of 10% hydrous methanol was heated under reflux for 2 hours. Ether was added to the reaction mixture, the insoluble matter was separated, the solution was washed with brine and then with an aqueous solution of ammonium sulfate, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 4: 1) to separate and purify the target compound (1).
And (2) were obtained.

Silica gel thin layer chromatography (developing solvent; hexane: ethyl acetate = 2: 1) Rf value of (1) = 0.48 Rf value of (2) = 0.40 NMR spectrum (δ _ppm , CDC ₃ ): (1) 1.01 ( 6H, d, J = 6Hz), 1.84 (2H, s), 1.6−2.1 (1H, nd), 2.12 (3H, s), 2.27 (3H, s), 2.58 (3H, s), 2.81 (1H, d, J = 19Hz), 3.00 (1H, d, J = 19Hz), 3.62 (3H, s), 4.14 (1H, d, J = 11Hz), 4.25 (1H, d, J = 11Hz), 4.89 (2H , s), 6.95 (2H, d, J = 4.5Hz), 8.20 (2H, d, J = 4.5Hz), (2) 0.98 (3H, d, J = 6Hz), 1.00 (3H, d, J = 6Hz), 1.80 (2H, d, J = 6Hz), 1.65−2.1 (1H, nd) 2.13 (3H, s), 2.23 (3H, s), 2.57 (3H, s), 2.82 (1H, d, J) = 14Hz), 3.00 (1H, d, J = 14Hz), 4.13 (1H, d, J = 12Hz), 4.27 (1H, d, J = 12Hz), 4.66 (1H, s), 6.95 (2H, d, J = 9Hz), 8.19 (2H, d, J = 9Hz).

Example 10 (D-2) 6-acetoxy-2-isobutyl-5,7,8-trimethyl-2- (4-nitrophenoxymethyl) chroman-4-
On 6-hydroxy-2-isobutyl-5,7,8-trimethyl-2- (4-nitrophenoxymethyl) chroman-4-
Acetic anhydride 3 in a mixture of 1.5 g of ON and 30 m of pyridine.
g, and the mixture was stirred at room temperature for 35 hours. The reaction mixture was concentrated, water was added, the mixture was extracted with ethyl acetate and benzene, 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 column chromatography (eluent; hexane: ethyl acetate = 5: 1) to obtain a target mixture.

Rf value of silica gel thin layer chromatography = 0.42 (developing solvent; hexane: ethyl acetate = 2: 1).

NMR spectrum (δ _ppm , CDC ₃ ): 1.01 (6H, d, J = 6Hz), 1.7−2.2 (3H, nd) 2.09 (3H, s), 2.12 (3H, s), 2.33 (3H, s), 2.42 (3H, s), 2.91 (2H, AB type, J = 18Hz), 4.13 and 4.25 (2H, AB type, J = 9Hz), 6.95 (2H, d, J = 9Hz), 8.20 (2H, d, J = 9Hz).

Example 11 (D-2) 6-acetoxy-2- (4-aminophenoxymethyl)
-2-isobutyl-5,7,8-trimethylchroman-4-
On 6-acetoxy-2-isobutyl-5,7,8-trimethyl-2- (4-nitrophenoxymethyl) chroman-4-
1.4 g of on was dissolved in 35 m of methanol and reduced under a hydrogen pressure of about 1 atm for 3 hours in the presence of 1 g of 10% palladium carbon. After removing the catalyst, the solvent was distilled off under reduced pressure to obtain the desired product.

Rf value of silica gel thin layer chromatography = 0.54 (developing solvent; ethyl acetate).

NMR spectrum (δ _ppm , CDC ₃ ): 0.97 (6H, d, J = 6Hz), 1.6-2.2 (3H, nd), 2.08 (3H, s), 2.14 (3H, s), 2.32 (3H, s) , 2.42 (3H, s), 2.74 and 3.02 (2H, AB type, J = 16Hz), 3.2−3.7 (2H, br.s), 3.9 and 4.06 (2H, AB type, J = 9Hz), 6.58 (2H , d, J = 9Hz), 6.73 (2H, d, J = 9Hz).

Example 12 (D-3) Ethyl 3- [4- (6-acetoxy-2-isobutyl-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy) phenyl] -2-chloropropionate 6- Acetoxy-2- (4-aminophenoxymethyl)
A mixture of 2-isobutyl-5,7,8-trimethylchroman-4-one (1.1 g) and acetone (20 m) was stirred at room temperature under a nitrogen stream at room temperature with concentrated hydrochloric acid (1.5 m), sodium nitrite (0.8 g) and water (0.8 g).
3 m was added, and further 4 g of ethyl acrylate was added.
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 sodium sulfate, 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 = 0.74 (developing solvent; hexane: ethyl acetate = 1: 2).

NMR spectrum (δ _ppm , CDC ₃ ): 0.98 (6H, d, J = 6Hz), 1.25 (3H, t, J = 7Hz), 1.5−2.2 (3H, nd), 2.08 (3H, s), 2.13 ( 3H, s), 2.32 (3H, s), 2.42 (3H, s), 2.78 and 3.01 (2H, AB type, J = 17Hz), 2.8−3.5 (2H, nd), 3.8−4.5 (2H, nd) , 6.82 (2H, d, J = 9Hz), 7.11 (2H, d, J = 9Hz).

Example 13 (D-4) 5- [4- (6-hydroxy-2-isobutyl-5,7,8
-Trimethyl-4-oxochroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione ethyl 3- [4- (6-acetoxy-2-isobutyl-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy) ) Phenyl] -2-chloropropionate 0.5
A mixture of g, 0.2 g of thiourea and 0.8 g of sulfolane is heated at 120-135 ° C for 4 hours under a nitrogen stream. Then, a mixture of concentrated hydrochloric acid 1 m, water 1 m, and ethylene glycol monomethyl ether 5 m was added to the reaction mixture, and the mixture was 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: 70-78 ° C. NMR spectrum _{(δ ppm, CDC 3):} 0.97 (6H, d, J = 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 = 16Hz), 2.8−3.2 (1H, nd), 3.41 (1H, dd, J = 4 and 14Hz), 4.06 (2H, AB type) , J = 10Hz), 4.43 (1H, dd, J = 4 and 9Hz), 4.6−5.3 (1H, br.s, lost by addition of heavy water), 6.81 (2H, d, J = 9Hz), 7.12 (2H, d, J = 9Hz), 8.7-9.3 (1H, br.s., disappeared by adding heavy water).

Example 14 (D-1) 6-hydroxy-2,5,7,8-tetramethyl-2- (4-
Nitrophenoxymethyl) chroman-4-one 2,5-dihydroxy-3,4,6-trimethylaethophenone
After leaving 3.9 g, 4-nitrophenoxyacetone 3.9 g, pyrrolidine 2.0 g and toluene 15 g at room temperature for 2 days,
Dilute hydrochloric acid is added to the reaction mixture and the mixture is 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 obtained residue, and the precipitated crystals are collected. Further, after subjecting to silica gel column chromatography (eluent; hexane: ethyl acetate = 5: 1), recrystallization from ethyl acetate gave the target compound.

Mp: 199-204 ° C. NMR spectrum _{(δ ppm, DMSO-d 6} ): 1.43 (3H, s), 2.01 (3H, s), 2.14 (3H, s), 2.46 (3H, s), 2.67 (1H, d, J = 16Hz), 3.03 (1H, d, J = 16Hz), 4.31 (2H, s), 7.19 (2H, d, J = 9Hz), 7.92 (1H, s), 8.21 (2H, d, J = 9Hz).

Example 15 (D-1) 6-acetoxy-2,5,7,8-tetramethyl-2- (4-
Nitrophenoxymethyl) chroman-4-one a) 5-acetoxy-2-hydroxy-3,4,6-trimethylacetophenone 17.7 g, 4-nitrophenoxyacetone 14.6 g, pyrrolidine 7.5 g and benzene 60 m The mixture was left standing at room temperature for 1 day and then heated under reflux for 7 hours using a water separator. Water and ethyl acetate were added to the reaction mixture,
The organic layer was separated and dried over anhydrous sodium sulfate.
The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 2:
Then, the target compound was obtained.

Rf value by silica gel thin layer chromatigraphy = 0.17
(Developing solvent; hexane: ethyl acetate = 3: 1) NMR spectrum (δ _ppm , CDC ₃ ): 1.56 (3H, s), 2.10 (6H, s), 2.36 (3H, s), 2.43 (3H, s) , 2.70 (1H, d, J = 15Hz), 3.06 (1H, d, J = 15Hz), 4.11 (1H, d, J = 10Hz), 4.24 (1H, d, J = 10Hz), 6.98 (2H, d) , J = 9Hz), 8.20 (2H, d, J = 9Hz).

b) The mixture in which piperidine was used instead of pyrrolidine in a) was heated to reflux for 3 hours using a water separator. 5% Hydrochloric acid was added to the reaction mixture and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The Rf value and NMR spectrum of the target compound obtained by distilling off the solvent are
Consistent with that in a).

c) The Rf value and the NMR spectrum of the target compound obtained in the same manner as in b) by using morpholine in place of piperindine in b) were the same as those in a).

d) In a), a mixture of morpholine in place of pyrrolidine and toluene in place of benzene was heated under reflux for 1 hour, and the Rf value and NMR spectrum of the target compound obtained in the same manner as in b) below are a). Coincided with that in.

Example 16 (D-1) 7-t-butyl-6-hydroxy-2-methyl-2-
(4-Nitrophenoxymethyl) chroman-4-one According to Example 14, 4-t-butyl-2,5-dihydroxyacetophenone 2.0 g, 4-nitrophenoxyacetone 1.9 g, pyrrolidine 1.0 The target compound produced from g and 10 m of benzene has the following physical properties.

Melting point: 205-209 ° C NMR spectrum (δ _ppm , deuterated acetone): 1.39 (3H, s), 1.53 (9H, s), 2.70 (1H, d, J = 16.5Hz), 3.05 (1H, d, J = 16.5Hz), 4.37 (2H, s), 6.80 (1H, s), 7.18 (2H, d, J = 10Hz), 7.22 (1H, s), 8.22 (2H, d, J = 10Hz), 8.21 (1H , s, disappears when heavy water is added).

Example 17 (D-2) 6-acetoxy-7-t-butyl-2-methoxy-2-
(4-Nitrophenoxymethyl) chroman-4-one 7-t-butyl-6-hydroxy-2-methyl-2-
(4-Nitrophenoxymethyl) chroman-4-one 1.
A mixture of 7 g, 1 m acetic anhydride and 10 m pyridine is left for 1 day at room temperature. Pour the reaction mixture into ice water, 2
After stirring for an hour, extract with benzene. 3 organic layers in sequence
It is washed with N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was benzene-ethyl acetate (about 10: 1).
The crystals were recrystallized from to obtain the target compound.

Melting point: 82-84 ° C NMR spectrum (δ _ppm , deuterated acetone): 1.33 (9H, s), 1.57 (3H, s), 2.33 (3H, s), 2.82 (1H, d, J = 16.5Hz), 3.13 (1H, d, J = 16.5Hz), 4.42 (2H, s), 6.93 (1H, s), 7.25 (2H, d, J = 9Hz), 7.44 (1H, s), 8.22 (2H, d, 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 -Tetramethyl-2- (4-
Nitrophenoxymethyl) chroman-4-one 1.8 g,
To a mixture of 15 m of methanol and 1 m of benzene, 160 mg of sodium borohydride was added under ice cooling, and the mixture was stirred 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, the residue was subjected to silica gel column chromatography (eluent; benzene: ethyl acetate = 9: 1), and the obtained crystals were recrystallized from a mixed solution of benzene and hexane to obtain the objective. The compound was obtained.

Mp: 139-141 ° C. NMR spectrum _{(δ ppm, CDC 3):} 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 = 9Hz), 5.0 (1H, dd, J = 3 and 9Hz), 7.03 (2H, d, J = 9Hz), 8.23 (2H, d, J = 9Hz).

Example 19 (F-1) 7-t-butyl-4,6-dihydroxy-2-methyl-2
-(4-Nitrophenoxymethyl) chroman 6-acetoxy-7-t-butyl-2-methyl-2-
(4-Nitrophenoxymethyl) chroman-4-one 3.
A solution of 0 g of THF (20 m) was added dropwise to a suspension of sodium borohydride (0.3 g) in methanol (10 m) under ice cooling and stirring. After completion of dropping, the mixture is stirred at room temperature for 2 hours. The mixture is ice-cooled again, made weakly acidic with 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer is washed with water and then 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 ° C NMR spectrum (δ _ppm , heavy acetone): 1.34 (9H, s), 1.50 (3H, s), 1.88 (1H, dd, J = 13.5 and 9Hz), 2.45 (1H, dd, J) = 13.5 and 6Hz), 2.78 (1H, s, disappears by adding heavy water), 4.15 (2H, s), 4.75 (1H, m), 6.62 (1H, s), 6.91 (1H, s), 7.15 (2H, d, J = 9Hz), 8.20 (2H, d, J = 9Hz).

Example 20 (F-2) 4,6-diacetoxy-7-t-butyl-2-methyl-2
-(4-Nitrophenoxymethyl) chroman 7-t-butyl-4,6-dihydroxy-2-methyl-2
3m of acetic anhydride was added to a mixture of 20g of-(4-nitrophenoxymethyl) chroman and 20m of pyridine, and the mixture was heated at 50 ° C for 3 hours. Dissolve the reaction solution in benzene,
The extract is washed with 3N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a pale yellow oily target compound.

Rf value by silica gel thin layer chromatography = 0.62
(Developing solvent; benzene: ethyl acetate = 5: 1) NMR spectrum (δ _ppm , deuterated acetone): 1.31 (9H, s), 1.55 (3H, s), 1.77 (3H, s), 2.0-2.3 (1H, nd), 2.27 (3H, s), 2.4−2.7 (1H, nd), 4.20 and 4.38 (2H, AB type, J = 10Hz), 5.85−6.10 (1H, m), 6.87 (1H, s), 6.98 (1H, s), 7.20 (2H, d, J = 9Hz), 8.30 (2H, d, J = 9Hz).

Example 21 (F-4) 6-acetoxy-7-t-butyl-2-methyl-2-
(4-Nitrophenoxymethyl) -2H-chromene 4,6-diacetoxy-7-t-butyl-2-methyl-2
-(4-Nitrophenoxymethyl) chroman 2.4 g, p
-Toluenesulfonic acid-hydrate 0.1 g, and benzene 50
The mixture of m is heated to 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 distilled off under reduced pressure to obtain a yellow oily target compound.

Rf value by silica gel thin layer chromatography = 0.58
(Developing solvent; benzene: ethyl acetate = 10: 1) NMR spectrum (δ _ppm , heavy acetone): 1.27 (9H, s), 1.54 (3H, s), 2.27 (3H, s), 4.28 (2H, s) , 5.79 (1H, d, J = 10Hz), 6.52 (1H, d, J = 10Hz), 6.67 (1H, s), 6.76 (1H, s), 7.13 (2H, d, J = 9Hz), 8.20 ( 2H, d, J = 9Hz).

Example 22 (F-3) 6-acetoxy-2,5,7,8-tetramethyl-2- (4-
Nitrophenoxymethyl) -2H-chromene According to Example 21, 6-acetoxy-4-hydroxy-
2,5,7,8-Tetramethyl-2- (4-nitrophenoxymethyl) chroman 160mg, p-toluenesulfonic acid 10m
The target compound produced from g and benzene 2m has the following physical properties.

Rf value of silica gel thin layer chromatography = 0.49 (developing solvent; benzene: ethyl acetate = 20: 1) NMR spectrum (δ _ppm , CDC ₃ ): 1.59 (3H, s), 2.03 (3H, s), 2.05 ( 3H, s), 2.09 (3H, s), 2.33 (3H, s), 4.10 (2H, AB type, J = 9Hz), 5.73 (1H, d, J = 10Hz), 6.73 (1H, d, J = 10Hz), 6.96 (2H, d, J = 9Hz), 8.22 (2H, d, J = 9Hz).

Example 23 (F-5) 6-acetoxy-2- (4-aminophenoxymethyl)
-7-t-Butyl-2-methylchroman 6-acetoxy-7-t-butyl-2-methyl-2-
(4-Nitrophenoxymethyl) -2H-chromene 2.1 g
To a mixture of 20 m benzene and 2 m acetic acid,
In the presence of 0.1 g of 10% palladium carbon, room temperature, hydrogen pressure of about 1
Reduced at atmospheric pressure for 10 hours. After removing the catalyst, the benzene solution is washed with saturated aqueous sodium hydrogencarbonate solution, then with water, 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) to obtain a light brown oily target compound.

Rf value of silica gel thin layer chromatography = 0.13 (developing solvent; benzene: ethyl acetate = 10: 1) NMR spectrum (δ _ppm , deuterated acetone): 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 adding heavy water), 6.50− 7.05 (6H, m).

Example 24 (F-5) 6-acetoxy-2- (4-aminophenoxymethyl)
-2,5,7,8-Tetramethylchroman According to Example 23, 6-acetoxy-2,5,7,8-tetramethyl-2- (4-nitrophenoxymethyl) -2H-chromene 100 mg. Was dissolved in 2 m of methanol and reduced in the presence of 20 mg of 10% palladium-carbon at a hydrogen pressure of about 1 atm to give the target compound having the following physical properties.

Mp: 138-140 ° C. NMR spectrum _{(δ ppm, CDC 3):} 1.42 (3H, s), 2.00 (3H, s), about 2 (2H, m), 2.04 (3H, s), 2.10 (3H, s ), 2.31 (3H, s), 2.6 (2H, br.t, J = 6Hz), 3.37 (2H, br. Disappeared by adding heavy water), 3.80 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) Ethyl 3- [4- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] 2-
Chloropropionate 6-acetoxy-2- (4-aminophenoxymethyl)
−2,5,7,8-Tetramethylchroman 17.5 g with acetone 130
dissolved in a mixed solvent of 30m and 30m of water and concentrated hydrochloric acid under ice-cooling 13
Then, 4.3 g of sodium nitrite is dissolved in 8.5 m of water and added dropwise. Further, 37.3 m of ethyl acrylate was added dropwise, the temperature was adjusted to 40 to 43 ° C., and 680 mg of cuprous oxide was gradually added. Generation of nitrogen is completed in about 30 minutes. Benzene is added to the reaction mixture forming two layers to extract the organic layer, the benzene extract is washed with saturated saline, dried over sodium sulfate, and the solvent is distilled off. The obtained black-brown oil was subjected to silica gel column chromatography, eluted with benzene-cyclohexane (1: 1 V / V), and then the same (2:
1V / V) Further elute with benzene. The target compound was obtained from the portion eluted with benzene to cyclohexane (2: 1 V / V) and benzene.

Rf value by silica gel thin layer chromatography = 0.39
(Developing solvent; benzene: ethyl acetate = 20: 1).

NMR spectrum (δ _ppm , CDC ₃ ): 1.23 (3H, t, J = 7.5Hz), 1.42 (3H, s), about 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 (1H, dd, J = 15 and 7.5Hz), 3.31 (1H, dd, J = 15 and 7.5Hz), 3.83 and 3.99 (2H, AB type, J = 9Hz), 4.18 (2H, q, J = 7.5Hz), 4.38 (1H, t, J = 7.5Hz), 6.85 (2H, d, J = 9Hz), 7.14 (2H, d, J = 9Hz).

Example 26 (A-4) Ethyl 3- [4- (6-acetoxy-7-t-butyl-2-methylchroman-2-ylmethoxy) phenyl]
2-Chloropropionate According to Example 25, 1.74 g of 6-acetoxy-2- (4-aminophenoxymethyl) -7-t-butyl-2-methylchroman, 380 mg of sodium nitrite, 0.8% of concentrated hydrochloric acid. m,
The pale yellow oily target compound produced from 4.5 g of ethyl acrylate, 65 mg of cuprous oxide, and 17 m of acetone has the following physical properties.

R _f value by silica gel thin layer chromatigraphy = 0.55
(Developing solvent; benzene: ethyl acetate = 5: 1) NMR spectrum (δ _ppm , CDC ₃ ): 1.23 (3H, t, J = 7.5Hz), 1.31 (9H, s), 1.45 (3H, s), 1.63 −2.20 (2H, m), 2.28 (3H, s), 2.72 (2H, br.t, J = 7Hz), 3.08 (1H, dd, J = 7.5 and 15Hz), 3.30 (1H, dd, J = 7.5) And 15Hz), 3.88 and 3.98 (2H, AB type, J = 9Hz), 4.18 (2H, q, J = 7.5Hz), 4.37 (1H, t, J = 7.5Hz), 6.73 (1H, s), 6.85 (1H, s), 6.88 (2H, d, J = 9Hz), 7.15 (2H, d, J = 9Hz).

Example 27 (A-5) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2-iminothiazolidin-4-one (a) and 5 -[4- (6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione (b) ethyl 3- [4- (6-acetoxy-2, 5,7,8-Tetramethylchroman-2-ylmethoxy) phenyl] -2
A mixture of 9.6 g of chloropropionate, 1.8 g of thiourea, 11 m of sulfolane is heated at 115-120 ° C. for 80 minutes in a nitrogen stream. After that, 90m of acetic acid and 30m of concentrated hydrochloric acid were added to the reaction mixture.
, And a mixture of 15m of water, and then at 85-90 ℃
Heat for 12 hours. 27 g of sodium hydrogen carbonate in the reaction mixture
After the generation of carbon dioxide gas is completed, the solvent is distilled off. 10: 1 (V / V) of benzene and ethyl acetate to the crude product
Add the mixed solvent and wash with saturated aqueous sodium hydrogen carbonate: water (1: 1, V / V). Take the white powder produced,
Further, it was washed with water and recrystallized from acetone to obtain the target compound (a).

Mp: 205-207 ° C. NMR spectrum _{(δ ppm, d 7 -dmf +} D 2 O): 1.37 (3H, s), about 2 (2H, m), 2.02 (3H, s), 2.14 (6H, s) , (2.3-3.1, solvent absorption), 3.42 (1H, dd, J = 15 and 4.5Hz), 4.60 (1H, dd, J = 9 and 4.5Hz), 6.93 (2H, d, J = 9Hz), 7.23 (2H, d, J = 9Hz).

The organic layer obtained by removing the white powder was washed with water,
It is dried over sodium sulfate and the solvent is distilled off. The obtained crude product was subjected to silica gel column chromatography and eluted with benzene: ethyl acetate (10: 1 V / V),
Then, the target compound (b) was obtained from the portion eluted with benzene: ethyl acetate (10: 1.4).

Melting point: 184-186 ° C NMR spectrum (δ _ppm , deuterated acetone): 1.39 (3H, s), about 2 (2H, m), 2.02 (3H, s), 2.09 (3H, s), 2.13 (3H, s) ), 2.63 (2H, br.t, J = 6Hz), 3.07 (1H, dd, J = 15 and 9Hz), 3.41 (1H, dd, J = 15 and 4.5Hz), 3.97 (2H, AB type, J = 9Hz), 4.70 (1H, dd, J = 9 and 4.5Hz), 6.90 (2H, d, J = 9Hz), 7.21 (2H, d, J = 9Hz).

Example 28 (A-5) 5- [4- (6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione ethyl 3- [4- ( 6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) phenyl] 2-
A mixture of 9.6 g of chloropropionate, 1.8 g of thiourea and 11 m of sulfolane is heated at 120 ° C. for 3.5 hours in a nitrogen stream. Then ethylene glycol monomethyl ether
Add 100m, 70m of 10% hydrochloric acid and heat to reflux for 12 hours.
The target compound was obtained by the same treatment and purification as in Example 27. The melting point and NMR spectrum were in agreement with those in Example 27.

Example 29 (A-5) 5- [4- (7-t-Butyl-6-hydroxy-2-methylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione According to Example 28, ethyl 3- [4- (6-acetoxy-7-t-butyl-2-methylchroman-2-ylmethoxy) phenyl] -2-chloropropionate 1.43
g, thiourea 430 mg, and sulfolane 5 m were heated at 120 ° C. for 3.5 hours, then ethylene glycol monomethyl ether (15 m) and 10% hydrochloric acid (10 m) were added, and the mixture was heated under reflux for 13 hours to produce the target compound (pale yellow powder). It has the following physical properties.

R _f value by silica gel thin layer chromatography = 0.31
(Developing solvent; benzene: ethyl acetate = 5: 1) NMR spectrum (δ _ppm , CDC ₃ ): 1.37 (9H, s), 1.43 (3H, s), 1.63−2.30 (2H, m), 2.67 (2H, br.t, J = 7Hz), 3.07 (1H, dd, J = 9 and 15Hz), 3.45 (1H, dd, J = 4 and 15Hz), 3.87 and 3.97 (2H, AB type, J = 9Hz), 4.48 (1H, dd, J = 4 and 9Hz), 4.62 (1H, br.s, lost by addition of heavy water), 6.41 (1H, s), 6.78 (1H, s), 6.88 (2H, d, J = 9Hz) , 7.15 (2H, d, J = 9Hz), 8.40-8.93 (1H, br, disappeared by adding heavy water).

Example 30 (A-4 and A-5) n-Butyl 3- [4- (6-acetoxy-2,5,
7,8-Tetramethylchroman-2-ylmethoxy) phenyl] -2-bromopropionate and 5- [4-
(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2-iminothiazolidin-4-one 6-acetoxy-2- (4-aminophenoxymethyl)
To a mixture of 2,5,7,8-tetramethylchroman (50 g) and acetone (100 ml), hydrobromic acid (68.4 g) and sodium nitrite (10.3 g) were dissolved in water (26 ml) and added dropwise under ice cooling. Further, 173.4 g of n-butyl acrylate was added at room temperature, 1.9 g of cuprous oxide was gradually added, and the mixture was stirred for 4 hours. The reaction mixture was washed twice with saturated saline, and the organic layer was concentrated to dryness. 250 ml of methanol and 1 thiourea were added to the obtained blackish brown oil.
0.3 g and 11.1 g of anhydrous sodium acetate were added, and the mixture was heated under reflux for 8 hours. The reaction mixture was cooled, and the precipitated crystals were collected by filtration to give 5- [4- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2-iminothiazolidin-4-one. Was obtained (yield 70
%).

Melting point: 220-222 ° C Example 31 (A-4 and A-5) n-butyl 3- [4- (6-acetoxy-2,5,
7,8-Tetramethylchroman-2-ylmethoxy) phenyl] -2-bromopropionate and 5- [4-
(6-Acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2-iminothiazolidin-4-one In Example 30, cupric oxide was replaced with 1.9 g of cuprous oxide. If 1.1g is used and others are carried out similarly, 5- [4-
49.0 g of (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2-iminothiazolidin-4-one was obtained (yield 75%).

Example 32 (A-4 and A-5) n-Butyl 3- [4- (6-acetoxy-2,5,
7,8-Tetramethylchroman-2-ylmethoxy) phenyl] -2-bromopropionate and 5- [4-
(6-Acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2-iminothiazolidin-4-one In Example 30, cupric chloride was replaced with 1.9 g of cuprous oxide.・ If dihydrate 2.3g is used and others are performed in the same manner, 5
49.0 g of-[4- (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2-iminothiazolidin-4-one was obtained (yield 75
%).

Example 33 (A-4 and A-5) n-Butyl 3- [4- (6-acetoxy-2,5,
7,8-Tetramethylchroman-2-ylmethoxy) phenyl] -2-bromopropionate and 5- [4-
(6-Acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2-iminothiazolidin-4-one In Example 30, instead of 1.9 g of cuprous oxide, the second bromide was used. 5- [4-]
49.6 g of (6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] -2-iminothiazolidin-4-one was obtained (yield 76%).

Reference example 1. 5-acetoxy-4-t-butyl-2-hydroxyacetophenone 100 g of t-butylhydroquinone, 130 m of acetic anhydride, and 1 kg of boron trifluoride acetic acid complex salt (40%) were stirred and heated at 60 ° C for 2 hours. And then at 90 ℃ 2
Heat for hours. After cooling, the reaction mixture is poured into ice water 3 and extracted with benzene. The extract is washed successively with water, saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate and the solvent is distilled off. The obtained oily substance was subjected to silica gel column chromatography (eluent: benzene) to obtain the target compound.

Melting point: 86.5-87.5 ° C. Reference Example 2 5-acetoxy-2-hydroxy-3,4,6-trimethylacetophenone 1,2-dichloroethane 60 ml of anhydrous aluminum chloride powder 22 g and acetyl chloride 11.8 g were added and dissolved under a nitrogen stream. Then, 1.61 g of trimethylhydroquinone
A solution slurried with 16 ml of dichloroethane was added slowly. The mixture was heated and reduced for 10 hours, poured into ice water for liquid separation, then washed with 5% aqueous sodium hydrogen carbonate solution and water, and the organic layer was concentrated to dryness. After 50 ml of n-hexane was added to the obtained oil to crystallize it, it was collected by filtration to obtain 8.03 g of 5-acetoxy-2-hydroxy-3,4,6-trimethylacetophenone (yield 68%).

Melting point: 68-73 ° C Reference Example 3 (H-1) 5- [4- (4,6-dihydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4- Dione 5- [4- (6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy) benzyl]
450 mg of sodium borohydride was added to a mixture of thiazolidine-2,4-dione (278 mg) and methyl alcohol (9 m), and the mixture was stirred at room temperature for 2 hours. A 1% acetic acid aqueous solution is added to the reaction mixture, which is then neutralized with an aqueous potassium carbonate solution and extracted with ethyl acetate. The ethyl acetate solution is washed with water and then dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent; hexane: ethyl acetate = 5: 3) to obtain the target compound.

Melting point: 102-118 ° C NMR spectrum (δ _ppm , heavy acetone and heavy water): 1.52 (3H, s), 2.01 (3H, s), 2.13 (3H, s), 2.29 (3H, s), 1.9-2.5 ( 1H, nd), 2.9-3.6 (2H, m), 4.03 (2H, s), 3.9-4.5 (1H, nd), 4.6-5.1 (2H, m), 6.7-7.4 (4H, nd).

Reference Example 4 (H-2) 5- [4- (6-hydroxy-2,5,7,8-tetramethyl-2H-chromen-2-ylmethoxy) benzyl] thiazolidine-2,4-dione Example 22 According to the reaction conditions, 5- [4- (4,6-dihydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 140 m
The target compound prepared from g, p-toluenesulfonic acid 10 mg, benzene 10 m, and dimethylformamide 0.5 m has the following physical properties.

Softening point: 173-176 ° C NMR spectrum (δ _ppm , deuterated acetone): 1.50 (3H, s), 2.02 (3H, s), 2.12 (3H, s), 2.18 (3H, s), 3.06 (1H, dd) , J = 9Hz and 14Hz), 3.40 (1H, dd, J = 4Hz 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 = 9Hz), 7.19 (2H, d, J = 9Hz).

Reference Example 5 (H-3) 5- [4- (6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy) benzyl] thiazolidine-2,4-dione Under the reaction conditions of Example 23. Similarly, 5- [4- (6-hydroxy-2,5,7,8-tetramethyl-2H-chromen-2-ylmethoxy) benzyl] thiazolidine-2,4-dione 120
Dissolve mg in 4 m of methanol, 10% palladium on carbon 40
The melting point and NMR spectrum of the target compound obtained by reduction under hydrogen pressure of 3-5 atm in the presence of mg were in agreement with those in Example 27.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C07D 495/10 9165-4C

Claims (2)

[Claims] 1. A general formula [In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or a lower alkyl group, and R ³ may have a hydrogen atom, an aliphatic lower acyl group, an alicyclic acyl group or a substituent. An aromatic acyl group, a heterocyclic acyl group, an aromatic aliphatic acyl group which may have a substituent, a lower alkoxycarbonyl group or an aralkyloxycarbonyl group, R
⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkoxy group. n represents an integer of 1 to 3. ] A diazotized compound of the compound represented by the general formula and CH ₂ ═CH—A ′ [wherein A ′ represents a cyano group, a carboxy group, an alkoxycarbonyl group or a carbamoyl group. ] Acrylic acid derivative represented by [Wherein 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
Is a group having the same meaning as A ′ and a compound represented by the formula —COOM (wherein M represents an equivalent cation)], and the obtained compound is reacted with thiourea, and if necessary, further , A general formula characterized by being hydrolyzed [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n have the same meanings as described above, and Y and Z each have an oxygen atom or an imino group. ] The manufacturing method of the thiazolidine derivative represented by these. 2. General formula [In the formula, R ² represents a hydrogen atom or a lower alkyl group,
R ³ is a hydrogen atom, an aliphatic lower acyl group, an alicyclic acyl group, an aromatic acyl group which may have a substituent, a heterocyclic acyl group, an aromatic aliphatic acyl which may have a substituent Group, a lower alkoxycarbonyl group or an 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. ] And a compound represented by the general formula [In the formula, R ¹ is the same or different and represents a group having the same meaning as R ² described above, and n represents an integer of 1 to 3. ] By reacting a 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. ] The compound represented by the formula is produced, and the compound is reduced, and if necessary, acylated, the compound of the general formula [In the formula, R ³ ′ represents the same or different group having the same meaning as R ³ described above, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n have the same meanings as described above. ] The compound of the general formula [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n have the same meanings as described above. ] The compound of the general formula [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n have the same meanings as described above. ] The compound represented by the following formula is obtained, the compound is diazotized, and then CH ₂ ═CH—A ′ of the general formula [wherein A ′ represents a cyano group, a carboxy group, an alkoxycarbonyl group or a carbamoyl group. ] The acrylic acid derivative represented by [Wherein 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
Is a group having the same meaning as A ′ and a compound represented by the formula —COOM (wherein M represents an equivalent cation)], and the obtained compound is reacted with thiourea, and if necessary, further , A general formula characterized by being hydrolyzed [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n have the same meanings as described above, and Y and Z represent an oxygen atom or an imino group. ] The manufacturing method of the thiazolidine derivative represented by these.