JP2003292466A - Method for producing alkoxyquinone compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for simply producing an alkoxyquinone compound. <P>SOLUTION: This method for producing the alkoxyquinone compound comprises using a compound of general formula (1) (R<SP>2</SP>, R3<SP>3</SP>and R<SP>4</SP>are each H, an alkyl which may be substituted, an aryl or a heteroaromatic residue) in an excess amount over the equivalent amount of a compound of general formula (2) (R<SP>1</SP>is an alkyl which may be substituted) in the presence of an oxidizing agent and a Lewis acid to produce the alkoxyquinone compound of general formula (3). <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

The present invention relates to the chemical industry,
The present invention relates to a convenient method for producing an alkoxyquinone compound used as a drug or a synthetic intermediate.

[0002]

2. Description of the Related Art As a typical synthesis method of 2-alkoxy-1,4-benzoquinone, J. Org. Chem. (1982) 47 2
The method using chlorite described in 017 is mentioned. However, this method is a good method for synthesizing a 2-methoxy-1,4-benzoquinone compound, but an alkoxyl group derived from an alcohol having low water solubility cannot be introduced. It can also be synthesized by the method using a Flemmy salt described in J. Org. Chem. (1994) 59 6567. However, it is not a simple method because it is necessary to prepare the Fremy salt itself. See also Chem. Ber. (1887) 20 1121, Chem. Be.
According to r. (1902) 354193, it can be synthesized using potassium dichromate, but it is not preferable because the waste liquid of chromium has a large environmental load. As a method of synthesizing 2-alkoxy-1,4-benzoquinone having low water solubility, there is a method of synthesizing through several steps such as Tetrahedron (1998) 54 1943, but it is not preferable because it is complicated. As described above, conventionally, there has been no method for synthesizing a 2-alkoxy-1,4-benzoquinone compound having low water solubility simply and without putting much load on the environment.

[0003]

SUMMARY OF THE INVENTION It is, therefore, an object of the present invention to provide an efficient method for producing an alkoxyquinone compound used as a drug or a synthetic intermediate in the chemical industry.

[0004]

In view of such circumstances, the inventors of the present invention have conducted diligent research and as a result, as a result, in the presence of an oxidizing agent and a Lewis acid, the compound of the general formula (1) was converted into the compound of the general formula (2). The present invention has been completed by finding that an alkoxyquinone compound represented by the general formula (3) can be industrially advantageously obtained by using an excess equivalent amount based on the compound. That is, the present invention provides <1>
A method for producing an alkoxyquinone compound represented by the general formula (3), which comprises using the compound of the general formula (1) in excess equivalent to the compound of the general formula (2) in the presence of an oxidizing agent and a Lewis acid. It is provided.

[0005]

[Chemical 2]

(In the formula, R ¹ represents an alkyl group which may have a substituent, and R ² , R ³ and R ⁴ may each independently have a hydrogen atom or a substituent. Indicates an alkyl, aryl or heteroaromatic group.)

Further, the present invention provides <2> a method for producing an alkoxyquinone compound described in <1>, which is characterized by using silver oxide (I) as an oxidizing agent. Furthermore, the present invention provides a method for producing an alkoxyquinone compound according to <1> or <2>, characterized in that zinc (II) chloride is used as <3> Lewis acid.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The manufacturing method of the present invention will be described in detail. First, the raw material compounds and products used will be described in detail. First, the quinone compound represented by the general formula (1) will be described. In the general formula (1), R ² , R ³ , R
⁴ independently represent a hydrogen atom or an optionally substituted alkyl, aryl or heteroaromatic group, wherein the alkyl group may be a straight chain one,
It may have a branched chain and its carbon number is 1
-20 are preferable and 4-20 are more preferable. Specific examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, sec-butyl group, t
-Butyl group, pentyl group, hexyl group, heptyl group, n
-Octyl group, 2-ethylhexyl group, t-octyl group, nonyl group, decyl group, dodecyl group, tridecyl group,
Examples thereof include tetradecyl group, pentadecyl group, n-hexadecyl group, 2-hexyldecyl group, heptadecyl group, octadecyl group, nonadecyl group and icosyl group. Moreover, examples of the aryl group include a phenyl group and a naphthyl group. In addition, examples of the heteroaromatic group include a pyridyl group, a pyrimidyl group, a quinolyl group and the like. here
When R ² , R ³ and R ⁴ represent an alkyl group, an aryl group or a heteroaromatic group, the substitutable position of these groups,
Halogen atom, alkyloxy group, aryloxy group,
The alkylthio group, arylthio group, alkyl group, aryl group, amino group, nitro group, amide group, carbamoyl group, sulfonamide group, sulfamoyl group and the like may be substituted. R ³ and R ⁴ may combine with each other to form a ring.

R ² , R ³ and R ⁴ are hydrogen atom, methyl group, ethyl group, isopropyl group, t-butyl group, phenyl group, alkoxyphenyl group, aryloxyphenyl group, alkylthiophenyl group, arylthiophenyl A group and a halogenophenyl group are preferable, and a hydrogen atom, a methyl group, a t-butyl group, a phenyl group, an alkoxyphenyl group, a halogenophenyl group, and an alkoxypyridyl group are particularly preferable.

Specific examples of the compound represented by the general formula (1) used in the present invention are shown below, but the present invention is not limited thereto.

[0011]

[Chemical 3]

Next, the alcohol compound represented by the general formula (2) will be described. R ¹ represents an alkyl group which may have a substituent, and the alkyl group here may be a linear one or a branched one, and the carbon number thereof is 1 to 20 is preferable and 4 to 20 is more preferable. Specific examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, sec-
Butyl group, t-butyl group, pentyl group, hexyl group, heptyl group, n-octyl group, 2-ethylhexyl group, t
-Octyl group, nonyl group, decyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, n-hexadecyl group, 2-hexyldecyl group, heptadecyl group,
Examples thereof include an octadecyl group, a nonadecyl group, an icosyl group, a 2-ethylhexyl group, and a 3,5,5-trimethylhexyl group. Here, the alkyl group of R ¹ is a halogen atom, an alkyloxy group, an aryloxy group, an alkylthio group, an arylthio group, an alkyl group, an aryl group at a substitutable position,
It may be substituted with an amino group, a nitro group, an amide group, a carbamoyl group, a sulfonamide group, a sulfamoyl group or the like.

Specific examples of the compound represented by the general formula (2) used in the present invention are shown below, but the present invention is not limited thereto.

[0014]

[Chemical 4]

Next, an embodiment of the present invention will be described. First, the amount ratio of the reactants used will be described. It is necessary to use the ketone compound represented by the general formula (1) in excess equivalent to the alcohol compound represented by the general formula (2), but it is preferable to use 1.1 to 3.5 times equivalent amount, and particularly 1.5 to It is preferable to use 2.5 equivalents. If the amount of the ketone compound used is less than 1.1 equivalents, the purity of the target product will decrease. If the amount of the ketone compound used is more than 3.5 equivalents, the compound represented by the general formula (1) is wasted.

The oxidizing agent used in the present invention will be described. The oxidizing agent used here may be any oxidizing agent that can oxidize a hydroquinone compound into a quinone compound. Specific examples thereof include silver (I) oxide, perchlorate, mercury (II) bromide, manganese dioxide, cerium ammonium nitrate, pyridinium chlorochromate, tribromide salt, and dichromate. Preferred is silver oxide
(I), perchlorate and manganese dioxide are mentioned, and particularly preferable one is silver (I) oxide. The amount of the oxidant used is required to be 2 electrons with respect to the compound of the general formula (2). That is, a one-electron oxidant requires a molar amount of 2 times or more, and a two-electron oxidant requires a molar amount of 1 or more. In order to carry out the reaction in good yield, it is preferable to use a 1-30% excess of the calculated amount of the oxidizing agent. When it is less than 1%, the purity of the product is lowered due to side reaction, and when it is more than 30%, the oxidizing agent is wasted.

The Lewis acid used in the present invention will be described. This reaction proceeds in the presence of Lewis acid, and as the Lewis acid used here, titanium tetrachloride, tin tetrachloride,
Examples thereof include trifluoroborane, zinc chloride and compounds obtained by exchanging ligands of these compounds. Titanium tetrachloride, tin tetrachloride and zinc chloride are preferably used, and titanium tetrachloride and zinc chloride are particularly preferably used. If the addition amount of Lewis acid is small, the reaction time becomes remarkably long, and in a large excess, the Lewis acid is wasted. Therefore, the addition amount of Lewis acid is 0.1 times to 1.0 times the mol of the compound of the general formula (2). It is preferably used in the range. More preferably 0.3
The molar amount is from twice to 0.6 times.

The solvent used in the present invention preferably has low nucleophilicity. This is because if it has a nucleophilicity comparable to that of alcohol, it will react. Therefore, a preferable solvent is a nitrile compound having 1 to 4 carbon atoms represented by acetonitrile or propionitrile, or an amide compound having 3 to 8 carbon atoms represented by N, N-dimethylformamide or N, N-dimethylacetamide. , A sulfoxide compound having 2 to 6 carbon atoms, represented by dimethyl sulfoxide,
A sulfone compound having 2 to 6 carbon atoms, represented by sulfolane, tetrahydrofuran, an ether compound having 4 to 10 carbon atoms, represented by dioxane, ethyl acetate, an ester compound having 4 to 10 carbon atoms, represented by butyl acetate, benzene, It is a hydrocarbon compound having 6 to 10 carbon atoms represented by toluene. More preferred are acetonitrile, tetrahydrofuran and sulfolane, and particularly preferred is acetonitrile.

The amount of the solvent used is preferably such that the concentration of the quinone compound represented by the general formula (1) used is in the range of 1.0 mol / liter to 5.0 mol / liter. If the concentration is higher than this, the reaction liquid becomes viscous and stirring may become difficult, which is not preferable. On the other hand, if the concentration is lower than this, the productivity will be lowered.

The reaction is selected from the range of 3 hours to 24 hours in a state where the quinone compound represented by the general formula (1), the alcohol compound represented by the general formula (2), the oxidizing agent and the Lewis acid are mixed. It is desirable to carry out heating and stirring at a temperature selected from the range of 50 ° C. to 100 ° C. for a period of time. Generally, if the reaction temperature is high, the reaction is completed in a short time.

Specific examples of the alkoxyquinone compound represented by the general formula (3) which can be synthesized by the present invention are shown below, but the present invention is not limited thereto.

[0022]

[Chemical 5]

[0023]

EXAMPLES Examples of the present invention will be shown below, but the present invention is not limited thereto. Example 1 5.0 g of the compound (1-1), 3.3 g of the compound (2-8), 10.7 g of silver (I) oxide, 1.3 g of zinc chloride and 30 ml of acetonitrile are mixed and heated under reflux for 12 hours. The reaction solution is filtered to remove inorganic substances. After distilling off the solvent, the compound (1-1) is removed by sublimation at 80 ° C./20 mmHg. The residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate-hexane to obtain 6.0 g of the desired product (3-1) as yellow needle crystals in a yield of 52%. ¹ H-NMR (CDCl ₃ ) δ: 0.90 (9H,
s), 0.97 (3H, d), 1.10 (1H, d
d), 1.14 (1H, dd), 1.66-1.80.
(2H, m), 1.80-1.90 (1H, m), 3.
94 (2H, t), 5.94 (1H, s), 6.70
(2H, s)

Comparative Example 1 (J. Org. Chem. (1982) 47 2017
Was referred to. ) 2- (3,5,5-trimethylhexyloxy) phenol 7.1
g, 70 ml of water and 4.5 g of concentrated sulfuric acid are dispersed at room temperature. A solution prepared by dissolving 13.6 g of sodium chlorite in 40 ml of water was added dropwise. The reaction did not proceed under these conditions.

Comparative Example 2 (Improved Method Above) 2- (3,5,5-Trimethylhexyloxy) phenol 7.1
g, 70 ml of water, 4.5 g of concentrated sulfuric acid, and 20 ml of hexane are dispersed at room temperature. A solution prepared by dissolving 13.6 g of sodium chlorite in 40 ml of water was added dropwise. Stir for 30 minutes at room temperature, confirm the disappearance of raw materials,
Toluene was added for extraction, and the organic layer was concentrated. Compound
Although the formation of (3-1) was observed, it could not be purified because it gave a complicated mixture.

[0026]

According to the method of the present invention, an alkoxyquinone compound can be easily produced.

Claims (3)

[Claims] 1. An alkoxyquinone represented by the general formula (3), wherein the compound of the general formula (1) is used in excess equivalent to the compound of the general formula (2) in the presence of an oxidizing agent and a Lewis acid. Method of manufacturing compound. [Chemical 1] (In the formula, R ¹ represents an alkyl group which may have a substituent, R ² , R ³ and R ⁴ are each independently a hydrogen atom or an alkyl which may have a substituent, aryl Or represents a heteroaromatic group.) 2. The method for producing an alkoxyquinone compound according to claim 1, wherein silver (I) oxide is used as an oxidizing agent. 3. The method for producing an alkoxyquinone compound according to claim 1, wherein zinc (II) chloride is used as the Lewis acid.