JP2002275137A - Method for producing tetrahydronaphthalene derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an industrially advantageous method for producing a tetrahydronaphthalene derivative expressed by the general formula (4) (wherein, X<1> to X<4> are a halogen, an alkyl, an alkoxy, an aryl or OH). SOLUTION: This method for producing the tetrahydronaphthalene derivative of the general formula (4) is provided by reacting a compound of the general formula (1) (wherein, R<1> is an alkyl) with an alcohol in the presence of an acidic ion exchange resin to obtain a ketal compound of the general formula (2) (wherein, R<2> , R<3> are each an alkyl), then effecting a halogenating agent to it for obtaining a compound of the general formula (3) and performing an acid treatment of the obtained compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a tetrahydronaphthalene derivative.

[0002]

2. Description of the Related Art General formula (4) (Wherein X ¹ , X ² , X ³ and X ⁴ are the same or different and are each a hydrogen atom, a halogen atom, an alkyl group,
Represents an alkoxy group, an aryl group or a hydroxyl group. Further, X ² and X ³ may together represent a phthaloyl group. The tetrahydronaphthalene derivative represented by the formula (1) is useful as a pharmaceutical synthesis intermediate (for example,
8-29750, etc.).

As a method for producing the tetrahydronaphthalene derivative represented by the general formula (4), the general formula (1) (Wherein, R ¹ represents an alkyl group which may be substituted with a halogen atom, and X ¹ , X ² , X ³ and X ⁴ each have the same meaning as described above).
A method is known in which a ketal compound is obtained by reacting an alcohol with an alcohol in the presence of an organic acid such as p-toluenesulfonic acid, a halogenating agent is allowed to act on the ketal compound, and then an acid treatment is performed. JP-A-58-29750).
However, the compound represented by the general formula (1) is
When reacted with an alcohol in the presence of an organic acid, the desired ketal compound, and an amino compound in which an acyl group is eliminated from the acylamino group of the ketal compound is by-produced, so that the yield of the ketal compound is low, The yield of the final target, the tetrahydronaphthalene derivative represented by the general formula (4), was also low. In addition, since the by-product amino compound has an adverse effect on the reaction in the next step, it is necessary to separate and remove the amino compound by a complicated purification operation, and it cannot be said that the production method is necessarily industrially satisfactory. Was.

[0004]

SUMMARY OF THE INVENTION Under such circumstances,
The present inventors have found that the industrially advantageous general formula (4) (Wherein X ¹ , X ² , X ³ and X ⁴ are the same or different and are each a hydrogen atom, a halogen atom, an alkyl group,
Represents an alkoxy group, an aryl group or a hydroxyl group. Further, X ² and X ³ may together represent a phthaloyl group. The present inventors have conducted intensive studies on the method for producing the tetrahydronaphthalene derivative represented by the general formula (1). (Wherein, R ¹ represents an alkyl group optionally substituted by a halogen atom, and X ¹ , X ² , X ³ and X ⁴ each have the same meaning as described above) and an alcohol Are reacted in the presence of an acidic ion exchange resin to obtain a compound of the general formula (2) (Wherein R ¹ , R ² , R ³ , X ¹ , X ² , X ³ and X ⁴ are
Each has the same meaning as described above, and R ² and R ³ are the same or different and each represents an alkyl group. Here, R ² and R ³ may together form an alkylene group which may be substituted with an alkyl group. )
Is obtained by reacting a halogenating agent with the ketal compound represented by the general formula (3) (Wherein R ¹ , R ² , R ³ , X ¹ , X ² , X ³ and X ⁴ are
Each has the same meaning as above. ) And treating the compound represented by the general formula (3) with an acid to suppress the formation of by-products and to perform the above-mentioned general process in good yield without performing complicated purification operations on the way. Equation (4)
It has been found that a tetrahydronaphthalene derivative represented by or a salt thereof can be produced, and the present invention has been accomplished.

[0005]

That is, the present invention provides a compound represented by the following general formula (1): (Wherein, R ¹ represents an alkyl group which may be substituted with a halogen atom, and X ¹ , X ² , X ³ and X ⁴ are the same or different and each represent a hydrogen atom, a halogen atom, an alkyl group, An alkoxy group, an aryl group or a hydroxyl group, and X ² and X ³ may be taken together to represent a phthaloyl group) with an alcohol in the presence of an acidic ion exchange resin. Let the general formula (2) (Wherein, R ¹ , X ¹ , X ² , X ³ and X ⁴ each have the same meaning as described above, and R ² and R ³ are the same or different and each represents an alkyl group. R ²
And R ³ may together form an alkylene group which may be substituted with an alkyl group. Is obtained by reacting the ketal compound with a halogenating agent to obtain a ketal compound represented by the general formula (3) Wherein R ¹ , R ² , R ³ , X ¹ , X ² , X ³ and X ⁴ have the same meaning as described above, and are represented by the general formula (3). General formula (4), wherein the compound is treated with an acid. (Wherein X ¹ , X ² , X ³ and X ⁴ have the same meanings as described above), or a method for producing a tetrahydronaphthalene derivative or a salt thereof.

[0006]

DESCRIPTION OF THE PREFERRED EMBODIMENTS First, general formula (1) (Wherein, R ¹ represents an alkyl group which may be substituted with a halogen atom, and X ¹ , X ² , X ³ and X ⁴ are the same or different and each represent a hydrogen atom, a halogen atom, an alkyl group, A compound represented by an alkoxy group, an aryl group or a hydroxyl group (X ² and X ³ may be taken together to represent a phthaloyl group) (hereinafter abbreviated as compound (1)) and an alcohol Are reacted in the presence of an acidic ion exchange resin to obtain a compound of the general formula (2) ^{(Wherein, R 1, X 1, X} 2, X 3 and X ⁴ represents the same meaning as defined above, R ² and R ³ are each the same or different, represents an alkyl group. Here, R ² And R ³ may be taken together to form an alkylene group which may be substituted with an alkyl group.) (Hereinafter, abbreviated as ketal compound (2)). explain.

In the formula of the compound (1), R ¹ represents an alkyl group which may be substituted with a halogen atom. Examples of the alkyl group optionally substituted with a halogen atom include:
For example, a linear or branched alkyl having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Examples thereof include a chloromethyl group, a fluoromethyl group, a trifluoromethyl group and the like in which a hydrogen atom of the group and these alkyl groups is substituted by a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom. In the formula of the compound (1), X ¹ , X ² , X ³ and X ⁴ are the same or different and each represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, an aryl group or a hydroxyl group. Further, X ² and X ³ may together represent a phthaloyl group.

Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, and the like. sec-
Examples thereof include a linear or branched C1-C4 alkyl group such as a butyl group and a tert-butyl group. Examples of the alkoxy group include a methoxy group, an ethoxy group, and n-
Examples thereof include linear or branched alkoxy groups having 1 to 4 carbon atoms such as a propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group. Examples of the aryl group include a phenyl group and a naphthyl group.

As the compound (1), for example, N-
(2-acetyl-1,2,3,4-tetrahydro-2-
Naphthyl) acetamide, N- (2-acetyl-1,
2,3,4-tetrahydro-2-naphthyl) trifluoroacetamide, N- (2-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthyl)
Acetamide, N- (2-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthyl) trifluoroacetamide, N- (2-acetyl-5,8
-Dihydroxy-1,2,3,4-tetrahydro-2-
Naphthyl) acetamide, N- (2-acetyl-5,8
-Dihydroxy-1,2,3,4-tetrahydro-2-
Naphthyl) trifluoroacetamide, N- (2-acetyl-1,2,3,4-tetrahydro-2-naphthyl)
Propionamide, N- (2-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthyl) propionamide,

N- (2-acetyl-5,12-dihydroxy-6,11-dioxo-1,2,3,4,6,11
-Hexahydro-2-naphthacenyl) acetamide, N
-(2-acetyl-5,12-dihydroxy-6,11
-Dioxo-1,2,3,4,6,11-hexahydro-2-naphthacenyl) trifluoroacetamide, N-
(2-acetyl-5,12-dihydroxy-6,11-
Dioxo-1,2,3,4,6,11-hexahydro-
2-naphthacenyl) propionamide and the like.

Some of the compounds (1) have an asymmetric carbon. In the present invention, either optically active compounds alone or in a mixture are used.

Examples of the alcohols include monohydric alcohols such as methanol, ethanol, n-propanol and n-butanol, and glycols such as ethylene glycol, propylene glycol and neopentyl glycol.

The amount of the alcohol to be used is usually at least 2 times the molar amount of the compound (1) in the case of a monohydric alcohol, and usually 1 to 1 in the case of a glycol. Molar times or more. The upper limit of the amount of the alcohol used is not particularly limited, but if it is too large, the volumetric efficiency becomes poor or the economical disadvantage tends to occur.
Practically, it is 50 mole times or less based on the compound (1).

The acidic ion exchange resin may be any resin in which an acidic ion exchange group is bonded to a polymer substrate (resin). Among them, the acidic ion exchange group is a sulfonic acid group,
^{A +} form of a strongly acidic ion exchange resin is preferred. Examples of such acidic ion exchange resins include Amberlyst 15, Amberlite IR120B (all are Organo Corporation), PK-216, HPK55, SK-1B (all are Mitsubishi Chemical Corporation), Dowex MSC-1 and Dowex 50WX8 (both from Dow Chemical Company) and the like. Further, such an acidic ion exchange resin may be a gel type, a porous type or a high porous type.

If the amount of the acidic ion exchange resin is too small, the reaction hardly proceeds, and if it is too large, a reverse reaction is likely to occur.
It is usually 0.01 to 10 times by weight, preferably 0.05 to 5 times by weight, more preferably 0.1 to 2 times by weight.

The reaction of compound (1) with alcohols may be carried out without a solvent or in an organic solvent. The organic solvent is not particularly limited as long as it is a solvent inert to the reaction, and examples thereof include halogenated hydrocarbon solvents such as dichloroethane and chloroform, and aromatic hydrocarbon solvents such as toluene and xylene. The amount is not particularly limited.

This reaction is usually carried out by mixing the compound (1), alcohols, acidic ion exchange resin and, if necessary, an organic solvent, and the mixing order is not particularly limited.

In this reaction, water is by-produced as the reaction proceeds, so that the reaction proceeds more smoothly.
It is preferable to carry out the reaction while removing by-product water out of the reaction system. As a method for removing by-product water to the outside of the reaction system, for example, a method of performing a reaction in the presence of a dehydrating agent such as anhydrous sodium sulfate, anhydrous magnesium sulfate, molecular sieves, a method of removing by azeotropic dehydration, these methods And the like.

If the reaction temperature is too low, the reaction does not easily proceed, while if it is too high, the raw material or the product tends to be unstable.

After completion of the reaction, the acidic ion-exchange resin is deactivated from the reaction solution as it is or after deactivation with an organic base, removed by, for example, filtration, and then subjected to ordinary post-treatments such as concentration and crystallization. The desired ketal compound (2) can be taken out. Examples of the organic base used for the deactivation treatment of the acidic ion exchange resin include, for example, triethylamine, pyridine and the like. The amount of the organic base to be used is not particularly limited as long as it is sufficient to deactivate the acidic ion exchange resin used.

In this reaction, the ketal compound (2) which has been removed from the ketal compound (2), which has an adverse effect on the reaction in the next step, has a small amount of by-products of the amine compound from which the acyl group has been eliminated. And can be used in the next step as it is. Of course, when the solvent used in this step does not inhibit the reaction in the next step, the reaction solution from which the acidic ion exchange resin has been removed may be used as it is in the next step.

The ketal compound (2) thus obtained is, for example, N- [2- (1,1-dimethoxyethyl) -1,2,3,4-tetrahydro-2-naphthyl]
Acetamide, N- [2- (1,1-dimethoxyethyl) -1,2,3,4-tetrahydro-2-naphthyl]
Trifluoroacetamide, N- [2- (1,1-dimethoxyethyl) -5,8-dimethoxy-1,2,3,4
-Tetrahydro-2-naphthyl] acetamide, N-
[2- (1,1-dimethoxyethyl) -5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthyl]
Trifluoroacetamide, N- [2- (1,1-dimethoxyethyl) -5,8-dihydroxy-1,2,3,
4-tetrahydro-2-naphthyl] acetamide, N-
[2- (1,1-dimethoxyethyl) -5,8-dihydroxy-1,2,3,4-tetrahydro-2-naphthyl) trifluoroacetamide, N- [2- (1,1-
Dimethoxyethyl) -1,2,3,4-tetrahydro-
2-naphthyl] propionamide, N- [2- (1,1
-Dimethoxyethyl) -5,8-dimethoxy-1,2,2
3,4-tetrahydro-2-naphthyl] propionamide,

N- [2- (1,1-dimethoxyethyl)
-5,12-dihydroxy-6,11-dioxo-1,
2,3,4,6,11-hexahydro-2-naphthacenyl] acetamide, N- [2- (1,1-dimethoxyethyl) -5,12-dihydroxy-6,11-dioxo-1,2,3, 4,6,11-hexahydro-2-naphthacenyl] trifluoroacetamide, N- [2-
(1,1-dimethoxyethyl) -5,12-dihydroxy-6,11-dioxo-1,2,3,4,6,11-
Hexahydro-2-naphthacenyl] propionamide,

N- [2- (2-methyl-1,3-dioxolan-2-yl) -1,2,3,4-tetrahydro-
2-naphthyl] acetamide, N- [2- (2-methyl-1,3-dioxolan-2-yl) -1,2,3,4
-Tetrahydro-2-naphthyl] trifluoroacetamide, N- [5,8-dimethoxy-2- (2-methyl-
1,3-dioxolan-2-yl) -1,2,3,4-
Tetrahydro-2-naphthyl] acetamide, N-
[5,8-Dimethoxy-2- (2-methyl-1,3-dioxolan-2-yl) -1,2,3,4-tetrahydro-2-naphthyl] trifluoroacetamide, N-
[5,8-dihydroxy-2- (2-methyl-1,3-
Dioxolan-2-yl) -1,2,3,4-tetrahydro-2-naphthyl] acetamide, N- [5,8-dihydroxy-2- (2-methyl-1,3-dioxolan-2-yl)- 1,2,3,4-tetrahydro-2-naphthyl] trifluoroacetamide,

N- [5,12-dihydroxy-6,11
-Dioxo-2- (2-methyl-1,3-dioxolan-2-yl) -1,2,3,4,6,11-hexahydro-2-naphthacenyl] acetamide, N- [5,12
Dihydroxy-6,11-dioxo-2- (2-methyl-1,3-dioxolan-2-yl) -1,2,3
4,6,11-hexahydro-2-naphthacenyl] trifluoroacetamide, N- [5,12-dihydroxy-6,11-dioxo-2- (2-methyl-1,3-dioxolan-2-yl) -1 , 2,3,4,6,11-
Hexahydro-2-naphthacenyl] propionamide,

N- [2- (2-methyl-1,3-dioxan-2-yl) -1,2,3,4-tetrahydro-2
-Naphthyl] acetamide, N- [2- (2-methyl-
1,3-dioxan-2-yl) -1,2,3,4-tetrahydro-2-naphthyl] trifluoroacetamide, N- [2- (2-methyl-1,3-dioxane-2)
-Yl) -5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthyl] acetamide, N- [2-
(2-methyl-1,3-dioxan-2-yl) -5
8-dimethoxy-1,2,3,4-tetrahydro-2-
Naphthyl] trifluoroacetamide, N- [2- (2
-Methyl-1,3-dioxan-2-yl) -5,8-
Dihydroxy-1,2,3,4-tetrahydro-2-naphthyl] acetamide, N- [2- (2-methyl-1,
3-dioxan-2-yl) -5,8-dihydroxy-
1,2,3,4-tetrahydro-2-naphthyl] trifluoroacetamide,

N- [2- (2-methyl-1,3-dioxan-2-yl) -5,12-dihydroxy-6,11
-Dioxo-1,2,3,4,6,11-hexahydro-2-naphthacenyl] acetamide, N- [2- (2-
Methyl-1,3-dioxan-2-yl) -5,12-
Dihydroxy-6,11-dioxo-1,2,3,4
6,11-hexahydro-2-naphthacenyl] trifluoroacetamide, N- [2- (2-methyl-1,3-
Dioxan-2-yl) -5,12-dihydroxy-
6,11-dioxo-1,2,3,4,6,11-hexahydro-2-naphthacenyl] propionamide,

N- [2- (2,5,5-trimethyl-
1,3-dioxan-2-yl) -1,2,3,4-tetrahydro-2-naphthyl] acetamide, N- [2-
(2,5,5-trimethyl-1,3-dioxane-2-
Yl) -1,2,3,4-tetrahydro-2-naphthyl] trifluoroacetamide, N- [2- (2,5,
5-trimethyl-1,3-dioxan-2-yl)-
5,8-dimethoxy-1,2,3,4-tetrahydro-
2-naphthyl] acetamide, N- [2- (2,5,5
-Trimethyl-1,3-dioxan-2-yl) -5,
8-dimethoxy-1,2,3,4-tetrahydro-2-
Naphthyl] trifluoroacetamide, N- [2-
(2,5,5-trimethyl-1,3-dioxane-2-
Yl) -5,8-dihydroxy-1,2,3,4-tetrahydro-2-naphthyl] acetamide, N- [2-
(2,5,5-trimethyl-1,3-dioxane-2-
Yl) -5,8-dihydroxy-1,2,3,4-tetrahydro-2-naphthyl] trifluoroacetamide,

N- [2- (2,5,5-trimethyl-
(1,3-Dioxan-2-yl) -5,12-dihydroxy-6,11-dioxo-1,2,3,4,6,11
-Hexahydro-2-naphthacenyl] acetamide, N
-[2- (2,5,5-trimethyl-1,3-dioxan-2-yl) -5,12-dihydroxy-6,11-
Dioxo-1,2,3,4,6,11-hexahydro-
2-Naphthacenyl] trifluoroacetamide, N-
[2- (2,5,5-trimethyl-1,3-dioxan-2-yl) -5,12-dihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-2
-Naphthacenyl] propionamide and the like.

When an optically active substance is used as the compound (1), its steric shape is maintained, and a ketal compound having its steric shape is obtained.

Next, a halogenating agent is allowed to act on the obtained ketal compound (2) to obtain a compound of the general formula (3) (Wherein R ¹ , X ¹ , X ² , X ³ , X ⁴ , R ² and R ³ are
Each has the same meaning as above. The step of obtaining the compound represented by the formula (hereinafter abbreviated as compound (3)) will be described.

Examples of the halogenating agent include bromine, chlorine, N-bromosuccinimide, N-chlorosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin and the like. It is sufficient that the halogenating agent is used in an amount sufficient to halogenate the ketal compound (2). If the amount is too large, the product may be halogenated. For example, bromine, chlorine, N-bromosuccinimide , N-chlorosuccinimide or the like, the amount of the halogenating agent capable of halogenating one molecule of the substrate with respect to the ketal compound (2) is usually 1 to 1.5 times, preferably 1 to 1.5 times the amount of the ketal compound (2). ~ 1.2 mol times, for example, 1,
In the case of a halogenating agent capable of halogenating two molecules of a substrate with one molecule of 3-dibromo-5,5-dimethylhydantoin or the like, the amount of the halogenating agent to be used is generally 0.5 to 0.5% with respect to the ketal compound (2). It is 8 mole times, preferably 0.5 to 0.6 mole times.

This reaction is usually carried out in the presence of a solvent,
The solvent may be any solvent that does not inhibit the reaction, for example, dichloroethane, chloroform, carbon tetrachloride, halogenated hydrocarbon solvents such as chlorobenzene, tetrahydrofuran, ether solvents such as dioxane, hexane,
Aliphatic hydrocarbon solvents such as cyclohexane and heptane,
Acetone, ketone-based solvents such as methyl ethyl ketone, benzene, aromatic hydrocarbon-based solvents such as toluene, acetic acid and the like, the amount of which is used, taking into account the physical properties of the reaction solution,
It is usually 5-300 times the weight of the ketal compound (2).

The reaction temperature is usually in the range of 10 ° C. to the reflux temperature of the reaction solution.

Further, a radical initiator such as 2,2'-azobisisobutyronitrile and benzoyl peroxide may coexist in the reaction system, or the reaction system may be irradiated with visible light. When the radical initiator is used, the amount thereof is usually 0.01 to 1 based on the ketal compound (2).
The molar ratio is, preferably, 0.1 to 0.5.

The reaction is usually carried out by mixing the ketal compound (2) and the halogenating agent in a solvent. The mixing order is not particularly limited, but it is preferable to add a halogenating agent to the mixture of the ketal compound (2) and the solvent from the viewpoint of suppressing a side reaction. The halogenating agent may be added all at once, but it is easy to control the reaction,
From the viewpoint of suppressing the generation of by-products and the like, it is preferable to add them separately.

In addition, since this reaction is a radical reaction, if oxygen or a solvent that inhibits the radical reaction is present in the reaction system, the reaction becomes difficult to proceed. It is preferable to remove the solvent and the like. In addition, hydrogen halide by-produced in the reaction also easily causes a side reaction and easily inhibits the reaction. Therefore, when performing the reaction, the reaction solution is bubbled with an inert gas such as nitrogen gas. For example, it is preferable to remove by-product hydrogen halide out of the reaction system.

After completion of the reaction, the compound (3) can be usually taken out by adding an aqueous alkali solution to the reaction solution, neutralizing the solution, separating the solution, and concentrating the resulting organic layer. Further, the acid treatment in the next step can be carried out as it is without taking out the compound (3) from the reaction solution after the reaction, but preferably the acid treatment in the next step is carried out after taking out the compound (3). Is preferred. In addition,
The removed compound (3) may be further purified by a usual purification means.

When an optically active substance is used as the ketal compound (2), its steric shape is maintained, and a compound (3) having its steric shape is obtained.

As the compound (3), for example, 2-
(1,1-dimethoxyethyl) -2,4- (1-aza-
3-oxa-2-methyl-1-propenyl) -1,2,2
3,4-tetrahydronaphthalene, 2- (1,1-dimethoxyethyl) -2,4- (1-aza-3-oxa-2
-Trifluoromethyl-1-propenyl) -1,2,2.
3,4-tetrahydronaphthalene, 2- (1,1-dimethoxyethyl) -2,4- (1-aza-3-oxa-2
-Methyl-1-propenyl) -5,8-dimethoxy-
1,2,3,4-tetrahydronaphthalene, 2- (1,
1-dimethoxyethyl) -2,4- (1-aza-3-oxa-2-trifluoromethyl-1-propenyl)-
5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, 2- (1,1-dimethoxyethyl) -2,4
-(1-aza-3-oxa-2-methyl-1-propenyl) -5,8-dihydroxy-1,2,3,4-tetrahydronaphthalene, 2- (1,1-dimethoxyethyl)
-2,4- (1-Aza-3-oxa-2-trifluoromethyl-1-propenyl) -5,8-dihydroxy-
1,2,3,4-tetrahydronaphthalene, 2- (1,
1-dimethoxyethyl) -2,4- (1-aza-3-oxa-2-ethyl-1-propenyl) -1,2,3,4
-Tetrahydronaphthalene, 2- (1,1-dimethoxyethyl) -2,4- (1-aza-3-oxa-2-ethyl-1-propenyl) -5,8-dimethoxy-1,2,2
3,4-tetrahydronaphthalene,

2- (1,1-dimethoxyethyl) -2,
4- (1-aza-3-oxa-2-methyl-1-propenyl) -5,12-dihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydronaphthacene, 2 -(1,1-dimethoxyethyl) -2,4- (1
-Aza-3-oxa-2-trifluoromethyl-1-propenyl) -5,12-dihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydronaphthacene, 2- ( 1,1-dimethoxyethyl) -2,4-
(1-Aza-3-oxa-2-ethyl-1-propenyl) -5,12-dihydroxy-6,11-dioxo-
1,2,3,4,6,11-hexahydronaphthacene,

2- (2-methyl-1,3-dioxolan-2-yl) -2,4- (1-aza-3-oxa-2-
Methyl-1-propenyl) -1,2,3,4-tetrahydronaphthalene, 2- (2-methyl-1,3-dioxolan-2-yl) -2,4- (1-aza-3-oxa-
2-trifluoromethyl-1-propenyl) -1,2,2
3,4-tetrahydronaphthalene, 2- (2-methyl-
1,3-dioxolan-2-yl) -2,4- (1-aza-3-oxa-2-methyl-1-propenyl) -5
8-dimethoxy-1,2,3,4-tetrahydronaphthalene, 2- (2-methyl-1,3-dioxolan-2-
Yl) -2,4- (1-aza-3-oxa-2-trifluoromethyl-1-propenyl) -5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, 2- (2
-Methyl-1,3-dioxolan-2-yl) -2,4
-(1-aza-3-oxa-2-methyl-1-propenyl) -5,8-dihydroxy-1,2,3,4-tetrahydronaphthalene, 2- (2-methyl-1,3-dioxolan-2 -Yl) -2,4- (1-Aza-3-oxa-2-trifluoromethyl-1-propenyl) -5,8
-Dihydroxy-1,2,3,4-tetrahydronaphthalene,

2- (2-methyl-1,3-dioxolan-2-yl) -2,4- (1-aza-3-oxa-2-
Methyl-1-propenyl) -5,12-dihydroxy-
6,11-dioxo-1,2,3,4,6,11-hexahydronaphthacene, 2- (2-methyl-1,3-dioxolan-2-yl) -2,4- (1-aza- 3-oxa-2-trifluoromethyl-1-propenyl) -5
12-dihydroxy-6,11-dioxo-1,2,2
3,4,6,11-hexahydronaphthacene, 2- (2
-Methyl-1,3-dioxolan-2-yl) -2,4
-(1-aza-3-oxa-2-ethyl-1-propenyl) -5,12-dihydroxy-6,11-dioxo-
1,2,3,4,6,11-hexahydronaphthacene,

2- (2-methyl-1,3-dioxane-
2-yl) -2,4- (1-aza-3-oxa-2-methyl-1-propenyl) -1,2,3,4-tetrahydronaphthalene, 2- (2-methyl-1,3-dioxane -2-yl) -2,4- (1-aza-3-oxa-2-
Trifluoromethyl-1-propenyl) -1,2,3
4-tetrahydronaphthalene, 2- (2-methyl-1,
3-dioxan-2-yl) -2,4- (1-aza-3
-Oxa-2-methyl-1-propenyl) -5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene,
2- (2-methyl-1,3-dioxan-2-yl)-
2,4- (1-aza-3-oxa-2-trifluoromethyl-1-propenyl) -5,8-dimethoxy-1,
2,3,4-tetrahydronaphthalene, 2- (2-methyl-1,3-dioxan-2-yl) -2,4- (1-
Aza-3-oxa-2-methyl-1-propenyl)-
5,8-dihydroxy-1,2,3,4-tetrahydronaphthalene, 2- (2-methyl-1,3-dioxane-
2-yl) -2,4- (1-aza-3-oxa-2-trifluoromethyl-1-propenyl) -5,8-dihydroxy-1,2,3,4-tetrahydronaphthalene,

2- (2-methyl-1,3-dioxane-
2-yl) -2,4- (1-aza-3-oxa-2-methyl-1-propenyl) -5,12-dihydroxy-
6,11-dioxo-1,2,3,4,6,11-hexahydronaphthacene, 2- (2-methyl-1,3-dioxan-2-yl) -2,4- (1-aza- 3-oxa-2-trifluoromethyl-1-propenyl) -5,1
2-dihydroxy-6,11-dioxo-1,2,3
4,6,11-hexahydronaphthacene, 2- (2-methyl-1,3-dioxan-2-yl) -2,4- (1
-Aza-3-oxa-2-ethyl-1-propenyl)-
5,12-dihydroxy-6,11-dioxo-1,
2,3,4,6,11-hexahydronaphthacene,

2- (2,5,5-trimethyl-1,3-
Dioxan-2-yl) -2,4- (1-aza-3-oxa-2-methyl-1-propenyl) -1,2,3,4
-Tetrahydronaphthalene, 2- (2,5,5-trimethyl-1,3-dioxan-2-yl) -2,4- (1
-Aza-3-oxa-2-trifluoromethyl-1-propenyl) -1,2,3,4-tetrahydronaphthalene, 2- (2,5,5-trimethyl-1,3-dioxan-2-yl) -2,4- (1-aza-3-oxa-2
-Methyl-1-propenyl) -5,8-dimethoxy-
1,2,3,4-tetrahydronaphthalene, 2- (2,
5,5-trimethyl-1,3-dioxan-2-yl)
-2,4- (1-aza-3-oxa-2-trifluoromethyl-1-propenyl) -5,8-dimethoxy-1,
2,3,4-tetrahydronaphthalene, 2- (2,5,
5-trimethyl-1,3-dioxan-2-yl)-
2,4- (1-aza-3-oxa-2-methyl-1-propenyl) -5,8-dihydroxy-1,2,3,4-
Tetrahydronaphthalene, 2- (2,5,5-trimethyl-1,3-dioxan-2-yl) -2,4- (1-
Aza-3-oxa-2-trifluoromethyl-1-propenyl) -5,8-dihydroxy-1,2,3,4-tetrahydronaphthalene,

2- (2,5,5-trimethyl-1,3-
Dioxan-2-yl) -2,4- (1-aza-3-oxa-2-methyl-1-propenyl) -5,12-dihydroxy-6,11-dioxo-1,2,3,4,6 ,
11-hexahydronaphthacene, 2- (2,5,5-trimethyl-1,3-dioxan-2-yl) -2,4-
(1-Aza-3-oxa-2-trifluoromethyl-1
-Propenyl) -5,12-dihydroxy-6,11-
Dioxo-1,2,3,4,6,11-hexahydronaphthacene, 2- (2,5,5-trimethyl-1,3-dioxan-2-yl) -2,4- (1-aza- 3-oxa-2-ethyl-1-propenyl) -5,12-dihydroxy-6,11-dioxo-1,2,3,4,6,1
1-hexahydronaphthacene and the like.

Finally, the compound (3) obtained above is treated with an acid to give a compound of the formula (4) (Wherein X ¹ , X ² , X ³ and X ⁴ each have the same meaning as described above) (hereinafter, tetrahydronaphthalene derivative (4)
Abbreviated. )) Or a process for producing the salt thereof.

By subjecting compound (3) to an acid treatment, a ring-opening reaction and a deketalization reaction progress, and the desired tetrahydronaphthalene derivative (4) or a salt of the tetrahydronaphthalene derivative (4) with the acid used Is obtained. Examples of the acid used for the acid treatment include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid, methanesulfonic acid, p-toluenesulfonic acid, and trifluoroacetic acid. The amount of the acid to be used is usually 1 mol or more per mole of the compound (3), and there is no particular upper limit. For example, acetic acid or the like may be used as a solvent. Since it is easy, it is practically 50 mole times or less.

When an inorganic acid is used as the acid, an aqueous solution of the inorganic acid is usually used, and its concentration is not particularly limited, but is usually 1 to 50% by weight in consideration of volumetric efficiency and the like. When an organic acid is used as the acid, it is usually used as it is or as a solution of a solvent described below.

The acid treatment is usually carried out with water, for example, an alcoholic solvent such as methanol, ethanol, isopropanol, n-butanol, etc .; an etheric solvent such as tetrahydrofuran, dioxane, etc .; It is carried out in a single or mixed solvent such as a hydrocarbon solvent, a ketone solvent such as acetone and methyl ethyl ketone. The amount of the solvent to be used is not particularly limited, but is usually 1 to 100 times by weight the compound (3) in consideration of the volume efficiency and the like.

The acid treatment temperature is usually in the range of 20 ° C. to the reflux temperature of the acid treatment solution.

After completion of the acid treatment, the tetrahydronaphthalene derivative (4) or a salt thereof can be taken out, for example, by cooling the acid treatment solution. The extracted tetrahydronaphthalene derivative (4) or a salt thereof may be further purified, for example, by recrystallization.

When a salt of the tetrahydronaphthalene derivative (4) and the used acid is obtained, the salt can be treated with an alkali such as an aqueous sodium hydroxide solution to obtain the tetrahydronaphthalene derivative (4). it can.

When an optically active substance is used as the compound (3), its steric shape is maintained, and the sterically-maintained tetrahydronaphthalene derivative (4) or a salt thereof is obtained.

The thus obtained tetrahydronaphthalene derivative (4) or a salt thereof includes, for example, 2-acetyl-2-amino-4-hydroxy-1,2,3,4-tetrahydronaphthalene, 2-acetyl-2-amino- 4
-Hydroxy-5,8-dimethoxy-1,2,3,4-
Tetrahydronaphthalene, 2-acetyl-2-amino-
4,5,8-trihydroxy-1,2,3,4-tetrahydronaphthalene, 2-acetyl-2-amino-4,
5,12-trihydroxy-6,11-dioxo-1,
2,3,4,6,11-hexahydronaphthacene, 2-
Acetyl-2-amino-4-hydroxy-1,2,3,
4-tetrahydronaphthalene hydrochloride, 2-acetyl-
2-amino-4-hydroxy-5,8-dimethoxy-
1,2,3,4-tetrahydronaphthalene hydrochloride, 2
-Acetyl-2-amino-4,5,8-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride,
2-acetyl-2-amino-4,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11
-Hexahydronaphthacene / hydrochloride.

By selecting reaction conditions such as acid treatment at a low temperature, for example, only the ring-opening reaction can be allowed to proceed. In this case, the compound (3) can be converted to a compound represented by the following general formula (5): (Wherein, R ² , R ³ , X ¹ , X ² , X ³ and X ⁴ have the same meanings as described above) (hereinafter abbreviated as compound (5)) or the compound A salt of (5) with the acid used is obtained. The obtained compound (5) or a salt thereof is deketalized by, for example, an acid treatment at a higher temperature to obtain a tetrahydronaphthalene derivative (4) or a salt thereof.

In order to produce the desired tetrahydronaphthalene derivative (4) with higher purity, the compound (3) is treated with an acid, for example, at a low temperature, and the compound (5) is once treated.
Alternatively, it is preferable to convert the compound (5) or a salt thereof to an acid treatment.

The compound (5) can be taken out, for example, by cooling the acid treatment solution. The extracted compound (5) may be further subjected to an acid treatment as it is, or may be further subjected to an acid treatment after being further purified by a usual purification means such as recrystallization. Needless to say, deketalization may be performed without removing compound (5) from the acid treatment solution.

When an optically active compound is used as the compound (3), its steric shape is maintained, and the compound (5) or its salt in which the steric shape is maintained is obtained.

The compound (5) or a salt thereof includes, for example, 2- (1,1-dimethoxyethyl) -2-amino-4-hydroxy-1,2,3,4-tetrahydronaphthalene, 2- (1, 1-dimethoxyethyl) -2-
Amino-4-hydroxy-5,8-dimethoxy-1,
2,3,4-tetrahydronaphthalene, 2- (1,1-
Dimethoxyethyl) -2-amino-4,5,8-trihydroxy-1,2,3,4-tetrahydronaphthalene,
2- (1,1-dimethoxyethyl) -2-amino-4,
5,12-trihydroxy-6,11-dioxo-1,
2,3,4,6,11-hexahydronaphthacene,

2- (2-methyl-1,3-dioxolan-2-yl) -2-amino-4-hydroxy-1,2,2
3,4-tetrahydronaphthalene, 2- (2-methyl-
1,3-dioxolan-2-yl) -2-amino-4-
Hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, 2- (2-methyl-1,3-dioxolan-2-yl) -2-amino-4,5,8-trihydroxy- 1,2,3,4-tetrahydronaphthalene, 2- (2-methyl-1,3-dioxolan-2-yl) -2-amino-4,5,12-trihydroxy-
6,11-dioxo-1,2,3,4,6,11-hexahydronaphthacene,

2- (2-methyl-1,3-dioxane-
2-yl) -2-amino-4-hydroxy-1,2,2
3,4-tetrahydronaphthalene, 2- (2-methyl-
1,3-dioxan-2-yl) -2-amino-4-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, 2- (2-methyl-1,3-dioxane-2 -Yl) -2-amino-4,5,8-trihydroxy-1,2,3,4-tetrahydronaphthalene,
2- (2-methyl-1,3-dioxan-2-yl)-
2-amino-4,5,12-trihydroxy-6,11
-Dioxo-1,2,3,4,6,11-hexahydronaphthacene,

2- (2,5,5-trimethyl-1,3-
Dioxan-2-yl) -2-amino-4-hydroxy-1,2,3,4-tetrahydronaphthalene, 2-
(2,5,5-trimethyl-1,3-dioxane-2-
Yl) -2-amino-4-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, 2-
(2,5,5-trimethyl-1,3-dioxane-2-
Yl) -2-amino-4,5,8-trihydroxy-
1,2,3,4-tetrahydronaphthalene, 2- (2,
5,5-trimethyl-1,3-dioxan-2-yl)
-2-amino-4,5,12-trihydroxy-6,1
1-dioxo-1,2,3,4,6,11-hexahydronaphthacene,

2- (1,1-dimethoxyethyl) -2-
Amino-4-hydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride, 2- (1,1-dimethoxyethyl) -2-amino-4-hydroxy-5,8-dimethoxy-1,2,3 , 4-Tetrahydronaphthalene hydrochloride, 2- (1,1-dimethoxyethyl) -2-amino-
4,5,8-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride, 2- (1,1-dimethoxyethyl) -2-amino-4,5,12-trihydroxy-6,11 -Dioxo-1,2,3,4,6,11-hexahydronaphthacene hydrochloride,

2- (2-methyl-1,3-dioxolan-2-yl) -2-amino-4-hydroxy-1,2,2
3,4-tetrahydronaphthalene hydrochloride, 2- (2-
Methyl-1,3-dioxolan-2-yl) -2-amino-4-hydroxy-5,8-dimethoxy-1,2,2
3,4-tetrahydronaphthalene hydrochloride, 2- (2-
Methyl-1,3-dioxolan-2-yl) -2-amino-4,5,8-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride, 2- (2-methyl-
1,3-dioxolan-2-yl) -2-amino-4,
5,12-trihydroxy-6,11-dioxo-1,
2,3,4,6,11-hexahydronaphthacene hydrochloride,

2- (2-methyl-1,3-dioxane-
2-yl) -2-amino-4-hydroxy-1,2,2
3,4-tetrahydronaphthalene hydrochloride, 2- (2-
Methyl-1,3-dioxan-2-yl) -2-amino-4-hydroxy-5,8-dimethoxy-1,2,3
4-tetrahydronaphthalene hydrochloride, 2- (2-methyl-1,3-dioxan-2-yl) -2-amino-4,
5,8-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride, 2- (2-methyl-1,3-dioxan-2-yl) -2-amino-4,5,12-tri Hydroxy-6,11-dioxo-1,2,3,4
6,11-hexahydronaphthacene hydrochloride,

2- (2,5,5-trimethyl-1,3-
Dioxan-2-yl) -2-amino-4-hydroxy-1,2,3,4-tetrahydronaphthalene hydrochloride,
2- (2,5,5-trimethyl-1,3-dioxane-
2-yl) -2-amino-4-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene.
Hydrochloride, 2- (2,5,5-trimethyl-1,3-dioxan-2-yl) -2-amino-4,5,8-trihydroxy-1,2,3,4-tetrahydronaphthalene.
Hydrochloride, 2- (2,5,5-trimethyl-1,3-dioxan-2-yl) -2-amino-4,5,12-trihydroxy-6,11-dioxo-1,2,3 4,
6,11-hexahydronaphthacene hydrochloride and the like.

As the acid used for treating the compound (5) with an acid to obtain the tetrahydronaphthalene derivative (4) or a salt thereof, the same acids as described above can be mentioned, and the amounts used thereof are also the same. The acid treatment is also usually carried out in the presence of a solvent, and examples of the solvent include the same ones as described above, and the amounts used thereof are also the same.

The acid treatment temperature is usually in a range from the temperature at which the deketalization reaction of the compound (5) proceeds to the reflux temperature of the reaction solution.

When an optically active substance is used as the compound (5), its steric shape is maintained, and the sterically-maintained tetrahydronaphthalene derivative (4) or a salt thereof is obtained.

[0072]

According to the present invention, it is possible to suppress the production of an amino compound which is by-produced in the ketalization step and inhibits the reaction in the next step. The tetrahydronaphthalene derivative can be produced efficiently and industrially advantageously.

[0073]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. The analysis was performed by high performance liquid chromatography.

Example 1 A reaction vessel was charged with N-[(2R) -2-acetyl-5,12
Dihydroxy-6,11-dioxo-1,2,3
4,6,11-Hexahydro-2-naphthacenyl] trifluoroacetamide 5.94 parts by weight, neopentyl glycol 8.36 parts by weight, Amberlyst 15 (Organo Co., Ltd.) 5.94 parts by weight and 1,2-dichloroethane 344.4 parts by weight were charged and refluxed for 16 hours (internal temperature: about 83 ° C.). The reflux liquid was passed through a vessel filled with 59.8 parts by weight of Molecular Sieves 4A, dehydrated, and then returned to the reaction vessel.

The reaction solution after refluxing for 16 hours was analyzed by high performance liquid chromatography to find that the desired ketal (N-[(2R) -5,12-dihydroxy-6,1) was obtained.
1-dioxo-2- (2,5,5-trimethyl-1,3
-Dioxan-2-yl) -1,2,3,4,6,11
-Hexahydro-2-naphthacenyl] trifluoroacetamide) has an LC area percentage of 96.5%, and an amine compound ((8R) -8-) from which a trifluoroacetyl group has been eliminated.
Amino-6,11-dihydroxy-8- (2,5,5-
Trimethyl-1,3-dioxan-2-yl) -7,
The LC area percentage value of (8,9,10-tetrahydro-5,12-tetracenedione) was less than 0.1%.

After completion of the reaction, 2.6 parts by weight of pyridine was added, Amberlyst 15 was separated by filtration, and the obtained filtrate was concentrated under reduced pressure. Methanol was added to the concentrated residue, and the mixture was again concentrated under reduced pressure to dryness. 237.9 parts by weight of methanol and 39.8 parts by weight of toluene were added thereto, and the mixture was refluxed for 1 hour, cooled to an internal temperature of 0 ° C., and the precipitated crystals were collected by filtration, washed, and dried under reduced pressure. Ketal body (N-
[(2R) -5,12-dihydroxy-6,11-dioxo-2- (2,5,5-trimethyl-1,3-dioxan-2-yl) -1,2,3,4,6,11 -Hexahydro-2-naphthacenyl] trifluoroacetamide) 6.38 parts by weight. Yield: 90.4% (N-
[(2R) -2-acetyl-5,12-dihydroxy-
6,11-dioxo-1,2,3,4,6,11-hexahydro-2-naphthacenyl] trifluoroacetamide.

An operation similar to this operation is performed three times, and N-
[(2R) -2-acetyl-5,12-dihydroxy-
From 6,41-dioxo-1,2,3,4,6,11-hexahydro-2-naphthacenyl] trifluoroacetamide 17.41 parts by weight (total) to N-[(2R) -5
12-dihydroxy-6,11-dioxo-2- (2,
5,5-trimethyl-1,3-dioxan-2-yl)
-1,2,3,4,6,11-hexahydro-2-naphthacenyl] trifluoroacetamide (18.66 parts by weight) (total). Yield: 89.9% (N-[(2R)-
2-acetyl-5,12-dihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-2
-Naphthacenyl] trifluoroacetamide standard).

The N-[(2R)-obtained above was added to the reaction vessel.
5,12-dihydroxy-6,11-dioxo-2-
(2,5,5-trimethyl-1,3-dioxane-2-
Yl) -1,2,3,4,6,11-hexahydro-2
-Naphthacenyl] trifluoroacetamide 6.28 parts by weight and chlorobenzene 573.8 parts by weight,
Under reduced pressure, about 85 parts by weight of the content liquid was concentrated and distilled off at an internal temperature of about 55 ° C. Thereafter, the internal temperature was raised to 75 to 80 ° C., and nitrogen bubbling was started. 30 minutes later, at the same temperature, 2, 2 '
-0.38 parts by weight of azobisisobutyronitrile was charged. After 5 minutes, 0.72 parts by weight of 1,3-dibromo-5,5-dimethylhydantoin was added after 25 minutes.
45 minutes later, 0.39 parts by weight of the same were charged and reacted. During this time, nitrogen bubbling continued. After completion of the reaction, 190.8 parts by weight of a 2% by weight aqueous sodium hydrogen carbonate solution was charged and subjected to liquid separation treatment to obtain an oil layer.
The oil layer was washed with 150.2 parts by weight of water, and then concentrated under reduced pressure.
2- (2,5,5-trimethyl-1,3-dioxane-
2-yl) -2,4- (1-Aza-3-oxa-2-trifluoromethyl-1-propenyl) -5,12-dihydroxy-6,11-dioxo-1,2,3,4,6 ,
8.74 parts by weight of 11-hexahydronaphthacene was obtained.

An operation similar to this operation was performed three times, and N-
[(2R) -5,12-dihydroxy-6,11-dioxo-2- (2,5,5-trimethyl-1,3-dioxan-2-yl) -1,2,3,4,6,11 -Hexahydro-2-naphthacenyl] trifluoroacetamide from 18.34 parts by weight (total) to 2- (2,5,5-trimethyl-1,3-dioxan-2-yl) -2,4-
(1-Aza-3-oxa-2-trifluoromethyl-1
-Propenyl) -5,12-dihydroxy-6,11-
23.12 parts by weight (total) of dioxo-1,2,3,4,6,11-hexahydronaphthacene were obtained.

In the reaction vessel, 2- (2,5,5) obtained above was added.
-Trimethyl-1,3-dioxan-2-yl) -2,
4- (1-aza-3-oxa-2-trifluoromethyl-1-propenyl) -5,12-dihydroxy-6,1
22.86 parts by weight of 1-dioxo-1,2,3,4,6,11-hexahydronaphthacene and 242.3 parts by weight of tetrahydrofuran were charged and refluxed (internal temperature: about 6).
6 ° C). To this, 55.6 parts by weight of 3.3% by weight hydrochloric acid aqueous solution were added.
It was added dropwise over 0 minutes. After the completion of the reaction, the mixture was cooled to an internal temperature of 0 ° C., and the precipitated crystals were collected by filtration, washed, and washed with 2- (2,5,5-
Trimethyl-1,3-dioxan-2-yl) -2-amino-4,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydronaphthacene.hydrochloric acid 23.78 parts by weight of salt (wet cake) was obtained.

The 2- (2,5,5) obtained above was placed in a reaction vessel.
-Trimethyl-1,3-dioxan-2-yl) -2-
23.73 parts by weight of amino-4,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydronaphthacene hydrochloride (wet cake),
135.3 parts by weight of water, 68.1 parts by weight of n-butanol and 53.9 parts by weight of 35% by weight hydrochloric acid were charged and refluxed (internal temperature: about 90 to 95 ° C.). After the reaction is completed, the internal temperature is 15
-20 ° C, and the precipitated crystals were collected by filtration, washed,
-Acetyl-2-amino-4,5,12-trihydroxy-6,11-dioxo-1,2,3,4,6,11-
Hexahydronaphthacene hydrochloride (wet cake) 1
7.7 parts by weight were obtained.

In a reaction vessel, 2-acetyl-2-amino-
4,5,12-trihydroxy-6,11-dioxo-
1,2,3,4,6,11-hexahydronaphthacene.
8.85 parts by weight of hydrochloride (wet cake) and 409.5 parts by weight of methanol were charged, and the pH was adjusted to 7.5 to 7.5 with an aqueous sodium hydroxide solution and an aqueous sodium hydrogen carbonate solution.
It was adjusted to 8.0. After raising the internal temperature to 35 to 40 ° C and keeping the temperature for 1 hour, the internal temperature was cooled to 0 ° C, and the precipitated crystals were collected by filtration, washed, and treated with 2-acetyl-2-amino-4,5,12-trihydroxy. -6,11-dioxo-1,2,3,4
4.74 parts by weight of 6,11-hexahydronaphthacene were obtained.

The same operation as this operation was performed twice, and 2-
(2,5,5-trimethyl-1,3-dioxane-2-
Yl) -2-amino-4,5,12-trihydroxy-
6,11-dioxo-1,2,3,4,6,11-hexahydronaphthacene hydrochloride (wet cake)
7 parts by weight (total) to 2-acetyl-2-amino-4,
5,12-trihydroxy-6,11-dioxo-1,
2,3,4,6,11-hexahydronaphthacene 9.5
7 parts by weight were obtained. Yield: 69.0% (N-[(2R)-
2-acetyl-5,12-dihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-2
-Naphthacenyl] trifluoroacetamide).

Comparative Example 1 N-[(2R) -2-acetyl-5,12 was added to a reaction vessel.
Dihydroxy-6,11-dioxo-1,2,3
4,6,11-Hexahydro-2-naphthacenyl] trifluoroacetamide (6.08 parts by weight), neopentyl glycol (4.26 parts by weight), methanesulfonic acid (0.46 parts by weight) and toluene (352.3 parts by weight) were charged, and the reaction mixture was charged. Was refluxed, and kept under reflux conditions for 10.5 hours (internal temperature: about 110 ° C.). During this time, the first 4 hours
An operation of removing a mixture of toluene and by-product water to the outside of the reaction system at a rate of about 48 parts by weight / hour and adding new toluene having the same weight as the mixture to the reaction system every hour is performed. About 4
Toluene was distilled off at a rate of 8 parts by weight / hour.

After the completion of the reaction, 0.51 parts by weight of pyridine was added, the mixture was stirred for 30 minutes, 192.3 parts by weight of toluene was added, and the mixture was cooled to an internal temperature of 70 ° C. Further, 24.3 parts by weight of anhydrous sodium sulfate and 18.3 parts by weight of silica gel were added, and the mixture was kept at the same temperature for 2 hours. Sodium sulfate and the like were separated by filtration, washed with warm toluene (about 70 ° C.), and the obtained filtrate was concentrated under reduced pressure to 40 parts by weight. Inner temperature 6
At 0 to 65 ° C, 240.9 parts by weight of methanol was added, the mixture was cooled to an internal temperature of 5 ° C, and the precipitated crystals were collected by filtration, washed, and further dried to obtain the desired ketal compound (N-[(2R)-
5,12-dihydroxy-6,11-dioxo-2-
(2,5,5-trimethyl-1,3-dioxane-2-
Yl) -1,2,3,4,6,11-hexahydro-2
-Naphthacenyl] trifluoroacetamide (5.57 parts by weight). Yield: 75.8% (N-[(2R) -2-
Acetyl-5,12-dihydroxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-2-naphthacenyl] trifluoroacetamide.

The N-[(2R)-obtained above was added to the reaction vessel.
5,12-dihydroxy-6,11-dioxo-2-
(2,5,5-trimethyl-1,3-dioxane-2-
Yl) -1,2,3,4,6,11-hexahydro-2
-Naphthacenyl] trifluoroacetamide (5.56 parts by weight) and toluene (284.3 parts by weight).
The temperature was raised to 0 ° C., 24.3 parts by weight of anhydrous sodium sulfate and 18.3 parts by weight of silica gel were added, the mixture was kept at the same temperature for 2 hours, filtered, and the filter residue was washed with hot toluene. The obtained filtrate was concentrated under reduced pressure to 35 parts by weight. 203.6 methanol at an internal temperature of 60 to 65 ° C.
The resulting crystals were collected by filtration, washed, and dried to obtain N-[(2R) -5,1.
2-dihydroxy-6,11-dioxo-2- (2,
5,5-trimethyl-1,3-dioxan-2-yl)
-1,2,3,4,6,11-hexahydro-2-naphthacenyl] trifluoroacetamide (5.46 parts by weight) was obtained. Yield: 75.4% (N-[(2R) -2-acetyl-5,12-dihydroxy-6,11-dioxo-
1,2,3,4,6,11-hexahydro-2-naphthacenyl] trifluoroacetamide standard).

The N-[(2R)-obtained above was added to the reaction vessel.
5,12-dihydroxy-6,11-dioxo-2-
(2,5,5-trimethyl-1,3-dioxane-2-
Yl) -1,2,3,4,6,11-hexahydro-2
-Naphthacenyl] trifluoroacetamide 5.40 parts by weight and chlorobenzene 493.5 parts by weight,
About 90 parts by weight of the content liquid was concentrated and removed under reduced pressure at an internal temperature of about 55 ° C. Thereafter, the internal temperature was raised to 65 to 70 ° C., and nitrogen bubbling was started. After 30 minutes, at the same temperature, 2,2 '
-0.32 parts by weight of azobisisobutyronitrile was charged. After 5 minutes, 0.63 parts by weight of 1,3-dibromo-5,5-dimethylhydantoin was added after 25 minutes.
45 minutes later, 0.34 parts by weight of the same were charged and reacted. During this time, nitrogen bubbling continued. After completion of the reaction, 160 parts by weight of a 2% by weight aqueous sodium hydrogen carbonate solution was charged and subjected to liquid separation treatment to obtain an oil layer. The oil layer was washed with 130 parts by weight of water and concentrated under reduced pressure. 7.6 parts by weight of tetrahydrofuran is charged to the concentrated residue, and the temperature is raised until reflux (internal temperature: about 66 ° C.).
6.5 parts by weight were added dropwise. After that, it was cooled to 0 ° C,
The precipitated crystals were collected by filtration, washed, and dried to give 2- (2,5,5)
-Trimethyl-1,3-dioxan-2-yl) -2,
4- (1-aza-3-oxa-2-trifluoromethyl-1-propenyl) -5,12-dihydroxy-6,1
There was obtained 4.09 parts by weight of 1-dioxo-1,2,3,4,6,11-hexahydronaphthacene hydrochloride. Yield: 6
2.3% (N-[(2R) -2-acetyl-5,12-
Dihydroxy-6,11-dioxo-1,2,3,4
6,11-hexahydro-2-naphthacenyl] trifluoroacetamide standard).

The 2- (2,5,5) obtained above was placed in a reaction vessel.
-Trimethyl-1,3-dioxan-2-yl) -2,
4- (1-aza-3-oxa-2-trifluoromethyl-1-propenyl) -5,12-dihydroxy-6,1
1-dioxo-1,2,3,4,6,11-hexahydronaphthacene hydrochloride 4.08 parts by weight, water 38.7 parts by weight, n-butanol 18.9 parts by weight and 35% by weight hydrochloric acid 15 .2 parts by weight and refluxed (internal temperature 90 to 9)
5 ° C). After completion of the reaction, the mixture was cooled to an internal temperature of 15 to 20 ° C., and the precipitated crystals were collected by filtration, washed and dried, and then 2-acetyl-2-amino-4,5,12-trihydroxy-6,11-dioxo-1. 2.99 parts by weight of 2,2,3,4,6,11-hexahydronaphthacene hydrochloride were obtained. Yield: 55.3%
(N-[(2R) -2-acetyl-5,12-dihydroxy-6,11-dioxo-1,2,3,4,6,11
-Hexahydro-2-naphthacenyl] trifluoroacetamide).

Continued on the front page (72) Inventor Kozo Shimago 3-1-198 Kasuganaka, Konohana-ku, Osaka City, Osaka Prefecture F-term (reference) 4H006 AA02 AC13 AC28 AC52 BA72 BB12 BB14 BB15 BB16 BB31 BE01 BE03 BE04 BJ50 BN20 BP90 BR20 4H039 CA61 CD10 CD90

Claims (1)

[Claims] 1. The general formula (1) (Wherein, R ¹ represents an alkyl group which may be substituted with a halogen atom, and X ¹ , X ² , X ³ and X ⁴ are the same or different and are each a hydrogen atom, a halogen atom, an alkyl group, An alkoxy group, an aryl group or a hydroxyl group, and X ² and X ³ may be taken together to represent a phthaloyl group) with an alcohol in the presence of an acidic ion exchange resin. Let the general formula (2) (Wherein, R ¹ , X ¹ , X ² , X ³ and X ⁴ each have the same meaning as described above, and R ² and R ³ are the same or different and each represents an alkyl group. R ²
And R ³ may together form an alkylene group which may be substituted with an alkyl group. Is obtained by reacting the ketal compound with a halogenating agent to obtain a ketal compound represented by the general formula (3) (Wherein R ¹ , R ² , R ³ , X ¹ , X ² , X ³ and X ⁴ are
Each has the same meaning as above. Wherein the compound represented by the general formula (3) is treated with an acid to obtain a compound represented by the general formula (4): (Wherein, X ¹ , X ² , X ³ and X ⁴ each have the same meaning as described above).