JPH05148175A - Production of p-dimethoxybenzene derivative - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as an intermediate for quinone compounds in high yield and at low cost by brominating a phenol derivative with bromine, reacting the reactional product with sodium methoxide to give a compound and reacting this compound with dimethyl sulfate. CONSTITUTION:A compound (e.g. 2,3,6-trimethoxy-p-cresol) of formula I (R<1>, R<3> and R<4> are methyl or methoxy; R<2> is H, methyl or methoxy with the proviso that when R<3> is not methoxy, R<2> and R<4> are methoxy) is reacted with dimethyl sulfate to give the objective compound of formula II (Me is methyl). The raw material compound of formula I is obtained by brominating a compound of formula III (Rb<1> to Rb<4> are H or methyl) such as 2,6-dimethylphenol with bromine and reacting the prepared compound of formula IV (Ra<1>, Ra<3> and Ra<4> are methyl or Br; Ra<2> is H, Br or methyl; when Ra<3> is not Br, Ra<2> and Ra<4> are both Br) with sodium methoxide.

Description

Detailed Description of the Invention

[0002]

[Industrial applications]

The present invention relates to a method for producing a p-dimethoxybenzene derivative. More specifically, it relates to an industrially useful method for producing a p-dimethoxybenzene derivative useful as an intermediate for a quinone compound.

[0004]

Prior Art and Problems to be Solved by the Invention CoQ
Many quinone compounds represented by are useful as medicines are known. For example, Japanese Patent Application No. 2-237051
In the issue,

[Chemical 10] Compounds represented by the following are disclosed as therapeutic agents for oral liver diseases, and Japanese Patent Application No. 3-44709 discloses:

[Chemical 11] Compounds represented by are disclosed as prophylactic / therapeutic agents for diseases in which leukotriene production inhibitory action and thromboxane A ₂ inhibitory action are effective.

Further, a quinone compound is also used as an intermediate in the benzothiazole derivative disclosed in Japanese Patent Application No. 3-71480 as a prophylactic / therapeutic agent for diseases for which leukotriene production inhibitory action or thromboxane A ₂ inhibitory action is effective. Plays an important role.

The p-dimethoxybenzene derivative is known as a very advantageous intermediate in the production of these quinone compounds.

Conventionally, the manufacturing has been performed by the following method.

[0008] J.Am.Chem.Soc. In 1987, 109 have been marked with a reaction of the following.

[Chemical 12]

[Chemical 13]

According to this method, dimethylbenzoquinone is reacted with acetic anhydride for acetylation, and the obtained acetylated product is reacted with dimethylsulfate in the presence of an alkali to obtain a target compound.

[0010]

[Means for Solving the Problems]

In view of such a situation, the inventors of the present invention have conducted earnest studies for a long time on an industrially advantageous manufacturing method which solves the above-mentioned drawbacks, but the method shown below is expected. The inventors have found that the object can be achieved and completed the present invention.

That is, the present invention is as follows:
It is a method for producing a p-dimethobenzene derivative comprising 3 steps. <First
Process>

[Chemical 14] <Second step>

[Chemical 15] <Third step>

[Chemical 16] (Where R ¹ , R ² , R ³ , R ⁴ , R ¹ _a , R ² _a , R ³ _a , R ⁴ _a , R
¹ _b , R ² _b , R ³ _b and R ⁴ _b have the above meanings. )

As the reaction solvent, any solvent that does not participate in the reaction can be used, but chloroform, ethyl acetate, acetone and the like are preferable. The reaction temperature is not particularly limited. The reaction temperature from the first step to the third step is about 3 to 6 hours. The final product is usually produced by silica gel chromatography or the like. The solvent is not particularly limited, but isopropyl ether-hexane or the like is preferable.

As described above, the method of the present invention is a method for obtaining a p-dimethoxybenzene derivative from an inexpensive and easily available raw material compound in a simple operation in a high yield. p-
Since the dimethoxybenzene derivative is a very useful compound in producing a quinone compound, the method of the present invention is also very useful mainly in producing a quinone compound useful as a pharmaceutical.

The method of the present invention is (i) easier and more reliable than the conventional method for producing a p-dimethoxybenzene derivative. (Ii) Very high yield. (iii) Raw materials are inexpensive and easily available. It can be said that it is a very advantageous method in industrial fields.

[0016]

【Example】

Examples of the present invention will be given below, but it goes without saying that the present invention is not limited to these examples. In the chemical structural formula, Me means a methyl group.

Example 1

2,5-dimethyl-1,3,4-trimethoxybenzene

[0020]

[Chemical 17]

(1) Production of 2,4-dibromo-3,6-dimethylphenol

[0022]

[Chemical 18]

200 g of 2,5-dimethylphenol was dissolved in 2 l of chloroform. This is ice-cooled and the internal temperature is 10 to 20 ° C.
The reaction was carried out by adding 537.2 g of bromine dropwise over 40 minutes so as to maintain the temperature at 50 ° C. After completion of dropping, stirring was continued for 1 hour to carry out a reaction. To the reaction mixture, 10% Na ₂ CO ₃ water 2l, CHCl ₃ 2l
Was added for extraction. The chloroform layer was concentrated, and the chloroform layer was concentrated under reduced pressure to obtain 492.1 g of a concentrated dry solid. To this was added 2.5 l of n-hexane for recrystallization. 393 g (yield: 85.7%) of crystals of the title compound were obtained.

(2) Production of 2,4-dimethoxy-3,6-dimethylphenol

[0025]

[Chemical 19]

2,4-dibromo-3,6 obtained in (1)
A mixture of 350 g of dimethylphenol, 50.1 g of copper iodide and 140 ml of dimethylfuran was heated to 60 ° C. and 1928.6 g of a 28% solution of sodium methoxide in methanol was injected at once. The reaction was advanced by gradually heating. Methanol started to distill from around 75 ° C, and foaming occurred around 85 ° C. The foaming was completed and the reaction was completed in about 30 minutes. After cooling, add 2 liters of water,
2 l of ethyl acetate was extracted. The aqueous layer was re-extracted with 2 l of ethyl acetate, the ethyl acetate layers were combined, and washed twice with 3 l of water each time. The ethyl acetate layer was concentrated under reduced pressure to obtain 250.3 g of the title compound.

(3) Production of 2,5-dimethyl-1,3,4-trimethoxybenzene

[0028]

[Chemical 20]

2,4-dimethoxy-3, obtained in (2),
250.3 g of 6-dimethylphenol was dissolved in 2 l of acetone, 82.3 g of potassium hydroxide was added, and 166 g of dimethylsulfate was added dropwise with stirring. The internal temperature rose from 20 to 50 ° and the reaction was completed in 30 minutes. 2 l of water and 2 l of dichloromethane were added to the reaction solution for extraction. The CH ₂ Cl ₂ layer was washed 3 times with 3 l of water each time, and the dichloromethane layer was concentrated under reduced pressure. Crude trimethoxy body 236g
Got 236 g of the obtained trimethoxy compound was added to 1.2 k of silica gel.
Subject to g column chromatography. n-hexane 5
1, 5% isopropyl ether-n-hexane 4 l, 10
% Isopropyl ether-n-hexane 2 l,
202 g of the title compound (yield: 85.6%) for concentrating the main fraction.
To get Oily substance.

¹ H-NMR (CDCl ₃ ) δ: 2.10 (3H, s),
2.26 (3H, s), 37.7 (6H, s), 3.82 (3H, s), 6.42 (1H,
s)

Example 2

2,6-dimethyl-1,4-dimethoxybenzene

[0033]

[Chemical 21]

(1) Production of 2,6-dimethyl-4-bromophenol

[0035]

[Chemical formula 22]

122 g of 2,6-dimethylphenol was dissolved in 1.2 l of chloroform. This is ice-cooled and the internal temperature is 10 ~
While maintaining the temperature at 20 ° C., 80 g of bromine was added dropwise over 40 minutes to carry out the reaction. After completion of dropping, stirring was continued for 1 hour to complete the reaction. The reaction mixture was extracted by adding 1.2 liter of 10% Na ₂ CO ₃ water and 1.2 liter of chloroform. The chloroform layer was separated and washed twice with 0.9 l of water, and the chloroform layer was concentrated under reduced pressure to obtain 205 g of a concentrated dry solid. 1.5 l of n-hexane was added to this and recrystallization was performed to obtain 171.0 g (yield: 85.0%) of 2,6-dimethyl-4-bromophenol.

(2) Production of 2,6-dimethyl-4-methoxyphenol

[0038]

[Chemical formula 23]

A mixture of 171.0 g of 2,6-dimethyl-4-bromophenol obtained in (1), 32.3 g of copper iodide and 68.4 ml of dimethylfuran was heated to 60 ° C. and 28% methanol of sodium methoxide was added. Inject 655.9 g of solution at once,
The reaction was advanced by gradually heating. Methanol started to distill from around 75 ° C, and foaming occurred around 85 ° C. The foaming was completed in about 30 minutes, and the reaction was completed. After cooling, add 1.4 l of water and extract with 1.4 l of ethyl acetate. The aqueous layer was re-extracted with 1.4 l of ethyl acetate, and the ethyl acetate layers were combined and washed twice with 2.1 l of water. Ethyl acetate was concentrated under reduced pressure to give 2,6-dimethyl-4.
152.2 g of methoxyphenol were obtained.

(3) Production of 2,6-dimethyl-1,4-dimethoxybenzene

[0041]

[Chemical formula 24]

152.2 g of 2,6-dimethyl-4-methoxyphenol obtained in (2) was dissolved in 1.2 l of acetone, 47.6 g of potassium hydroxide was added, and 112.9 g of dimethylsulfate was added dropwise with stirring. The internal temperature rose from 20 to 50 ° C, and the reaction was completed in 30 minutes.

1.2 l of water and 1.2 l of dichloromethane were added to the reaction solution.
Was added and extracted. The dichloromethane layer was washed with 1.8 l of water three times, and the dichloromethane layer was concentrated under reduced pressure. Get 126.9g.

126.9 g of the crude trimethoxy derivative obtained above was subjected to column chromatography on 635 g of silica gel. n-hexane 2.5l, 5% isopropyl ether-n-hexane 2.0l, 10% isopropyl ether-n-hexane 1
Elute with 1 and concentrate the main fraction. 107.9 g of the title compound
(Yield: 85.0%) was obtained. Oily substance.

¹ H-NMR (CDCl ₃ ) δ: 2.27 (6H, s),
3.68 (3H, s), 3.75 (3H, s), 6.56 (2H, s)

Example 3

2,3,4,5-tetramethoxytoluene

[0048]

[Chemical 25]

(1) Preparation of 2,3,5-tribromo-p-cresol

[0050]

[Chemical formula 26]

Chloroform 1.1 was added to 108.2 g of p-cresol.
dissolve in 1. This was ice-cooled and 239.7 g of bromine was added dropwise over 50 minutes while the internal temperature was kept at 10 to 20 ° C to carry out the reaction. After completion of the dropping, stirring was continued for 1 hour to carry out the reaction. The reaction mixture was extracted by adding 1 L of 10% Na ₂ CO ₃ water and 1 L of chloroform. Chloroform layer
It was washed twice with 0.8 l of water, and the chloroform layer was concentrated under reduced pressure to obtain 335.0 g of a concentrated dry solid. To this was added 1.7 l of n-hexane for recrystallization to give 282.8 g (86.0 g) of crystals of the title compound.
%) Was obtained.

(2) Preparation of 2,3,5-trimethoxy-p-cresol

[0053]

[Chemical 27]

2,3,5-tribromo-obtained in (1)
A mixture of 282.8 g of p-cresol, 32.8 g of copper iodide and 113 ml of dimethylfuran was heated and 1990 g of a 28% solution of sodium methoxide in methanol was injected at once. The reaction was advanced by gradually heating. Methanol started to distill from around 75 ° C, and foaming occurred around 85 ° C. The foaming ends in 30 minutes and the reaction ends. After cooling, add 1.6 l of water and extract with 1.6 l of ethyl acetate. The aqueous layer is re-extracted with 1.6 l of ethyl acetate, the ethyl acetate layers are combined and washed twice with 2.4 l of water.
The ethyl acetate layer is concentrated under reduced pressure to give 142.9 g (yield: 100%) of the title compound.

(3) Production of 2,3,4,5-tetramethoxytoluene

[0056]

[Chemical 28]

142.9 g of 2,3,5-trimethoxy-p-cresol obtained in (2) was dissolved in 1.2 l of acetone, 48.2 g of potassium hydroxide was added, and 108.4 g of dimethylsulfate was added dropwise with stirring. The internal temperature rose by 20 to 50 ° C. The reaction was completed in 30 minutes. 1.2 l of water and 1.2 l of dichloromethane were added to the reaction solution for extraction. The dichloromethane layer was washed 3 times with 1.8 l of water, and the dichloromethane layer was concentrated under reduced pressure. 148.1 g of crude tetramethoxy compound was obtained. Crude tetramethoxy body 148 obtained above.
1 g was subjected to column chromatography on 740 g of silica gel. n-hexane 3l, 5% isopropyl ether-n
-Elution with 2.4 l of hexane and 1.2 l of 10% isopropyl ether-n-hexane, and the main fraction was concentrated. 122.9 g (yield: 83.0%) of the title compound was obtained. Oily substance.

¹ H-NMR (CDCl ₃ ) δ: 2.20 (3H, s),
3.76 (3H, s), 3.80 (3H, s), 3.85 (3H, s), 3.90 (3H, s)
s), 6.37 (1H, s)

Next, an example of producing a quinone compound using the method of the present invention will be shown as a reference example.

[0060]

Reference Example (E) -3- [5- (2,3-dimethoxy-6-methyl-1,4-benzoquinoyl)]-2-nonyl-2-propenoic acid

[0061]

[Chemical 29]

(1) Production of 2,3,6-tribromo-p-cresol (method of the present invention)

[0063]

[Chemical 30]

216.4 g of p-cresol was added to chloroform 2.2.
It was dissolved in 1 and cooled with ice, and 479.4 g of bromine was added dropwise over 1 hour so that the internal temperature was kept at 10 to 20 ° C., and the reaction was carried out. After completion of the dropping, stirring was continued for 1 hour to carry out the reaction.
The reaction mixture was extracted by adding 2 L of 10% Na ₂ CO ₃ water and 2 L of chloroform. The chloroform layer was washed twice with 1.6 l of water, and the chloroform layer was concentrated under reduced pressure to obtain 670.0 g of a dried solid product. 1.7 l of n-hexane was added to this and recrystallization was carried out to obtain 282.8 g (yield: 86.0%) of crystals of the title compound.

(2) Production of 2,3,6-trimethoxy-p-cresol (method of the present invention)

[0066]

[Chemical 31]

2,3,6-tribromo-obtained in (1)
A mixture consisting of 565.6 g of p-cresol, 65.6 g of copper iodide and 226 ml of dimethylfuran was heated, and 3980 g of 28% methanol solution of sodium methoxide was injected at once. The reaction was advanced by gradually heating. Methanol started to distill from around 75 ° C, and foaming occurred around 85 ° C. Foaming ends in 45 minutes,
The reaction is complete. After cooling, add 3.2 liters of water and add ethyl acetate.
Extracted with 3.2 l. The aqueous layer was re-extracted with 3.2 l of ethyl acetate, and the ethyl acetate layers were combined and washed twice with 4.8 l of water.
Ethyl acetate was concentrated under reduced pressure to obtain 285.8 g (yield: 100%) of the title compound.

(3) Production of 2,3,4,5-tetramethoxytoluene (method of the present invention)

[0069]

[Chemical 32]

The 2,3,6-trimethoxy-p-cresol obtained in (2) was dissolved in 2.4 l of acetone, 96.4 g of potassium hydroxide was added, and 216.8 g of dimethylsulfate was added dropwise with stirring. The internal temperature rose from 20 to 50 ° C, and the reaction was completed in 30 minutes. 2.4 l of water and 2.4 l of dichloromethane were added to the reaction solution for extraction. The dichloromethane layer was washed 3 times with 3.6 l of water, and the dichloromethane layer was concentrated under reduced pressure. 296.2 g of crude tetramethoxy compound was obtained. This was subjected to column chromatography on 1480 g of silica gel. The main fraction was concentrated by eluting with 6 l of n-hexane, 4.8 l of 5% isopropyl ether-n-hexane and 2.4 l of 10% isopropyl ether-n-hexane. 245.8 g (yield: 83.0%) of the title compound was obtained. Oily substance.

(4) Preparation of 6-methyl-2,3,4,5-tetramethoxybenzaldehyde

[0072]

[Chemical 33]

150.0 g of 2,3,4,5-tetramethoxytoluene obtained in (3), trifluoroacetic acid (TFA)
After 1.8 l were mixed and uniformly dissolved, hexane methylene tetracine was added with stirring and the mixture was heated to 80 to 90 ° C. A heating reflux reaction was performed for 2 hours. Then, trifluoroacetic acid was distilled off by heating at atmospheric pressure. During distilling, the internal temperature gradually increased from 85 ° C, and distilling ended when it reached 110 ° C (distilled amount
900 ml). After cooling the concentrated solution, it was dissolved in 4 liters of water and basified to pH 8 with 577.6 g of anhydrous sodium carbonate. Then, the mixture was extracted with 2 l of ethyl acetate, the aqueous layer was re-extracted with 1 l of ethyl acetate, the ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound.
177.1 g (yield: 104%) was obtained.

(5) (E) -3- [5- (1-hydroxy-6-methyl-2,3,4-trimethoxy) phenyl]
Preparation of ethyl 2-nonyl-2-propenoate

[0075]

[Chemical 34]

6-methyl-2,3,4, obtained in (4)
5-Tetramethoxybenzaldehyde 177.1g, Ethyl 2-diethylphosphonoundecanoate 387.9g, Toluene
28% sodium methoxide methanol solution is added dropwise to 1.8 l of the mixed solution. The internal temperature rose by about 10 ° C. Then 55-60
The mixture was heated to ℃ and stirred. After reacting for about 3.5 hours, it was cooled. 1.8 l of isopropyl ether and 0.3 l of diethyl ether were added, and the mixture was washed with 3.6 l of water.

[Chemical 36]

[Chemical 35]

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] February 8, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 4

[Correction method] Change

[Correction content]

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 5

[Correction method] Change

[Correction content]

[Procedure 3]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 6

[Correction method] Change

[Correction content]

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0004

[Correction method] Change

[Correction content]

[0004]

2. Description of the Related Art Many quinone compounds represented by CoQ ₁₀ are known to be useful as pharmaceuticals. For example, in Japanese Patent Application No. 2-237051,

A compound represented by the formula: is disclosed as a therapeutic agent for oral liver disease, and Japanese Patent Application No. 3-44709 discloses that

The compound represented by the formula: is disclosed as a prophylactic / therapeutic agent for diseases in which the leukotriene production inhibitory action or thromboxane A ₂ inhibitory action is effective.

[Procedure Amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0009

[Correction method] Change

[Correction content]

According to this method, dimethylbenzoquinone is reacted with acetic anhydride to acetylate, and the obtained acetylated product is reacted with dimethylsulfate in the presence of an alkali to obtain a target compound. But when used in this way
The starting material, dimethylbenzoquinone, is expensive and
It's hard to handle. In addition, this method also yields a good final product.
Since it is not available, it is not suitable as an industrial method.
Absent.

[Procedure correction 6]

[Document name to be amended] Statement

[Correction target item name] 0013

[Correction method] Change

[Correction content]

As the reaction solvent, any solvent that does not participate in the reaction can be used, but chloroform, ethyl acetate, acetone and the like are preferable. The reaction temperature is not particularly limited. reaction
The time from the first step to the third step is about 3 to 6 hours. The final product is usually purified by silica gel chromatography or the like. The solvent is not particularly limited, but isopropyl ether-hexane or the like is preferable.

[Procedure Amendment 7]

[Document name to be amended] Statement

[Correction target item name] 0021

[Correction method] Change

[Correction content]

[0021] (1) 2,4-diblock mode-3,6-dimethyl - phenol

[Procedure Amendment 8]

[Document name to be amended] Statement

[Name of item to be corrected] 0023

[Correction method] Change

[Correction content]

[0023]
200 g of 2,5-dimethylphenol was dissolved in 2 l of chloroform. Cool this with ice and adjust the internal temperature to 10
The reaction was carried out by adding 537.2 g of bromine dropwise over 40 minutes so as to keep the temperature at -20 ° C. Add 2 l of 10% calcium carbonate water to the reaction mixture .
Extraction was carried out by adding 2 l of loroform . The chloroform layer was concentrated under reduced pressure to obtain 492.1 g of a concentrated dry solid. To this was added 2.5 l of n-hexane for recrystallization. 393 g (yield 85.7%) of crystals of the title compound were obtained.

[Procedure Amendment 9]

[Document name to be amended] Statement

[Correction target item name] 0026

[Correction method] Change

[Correction content]

[0026]
(1) obtained in 2,4-diblock mode -
A mixture of 350 g of 3,6-dimethylphenol, 50.1 g of copper iodide and 140 ml of dimethylfuran was heated to 60 ° C,
1928.6 with a 28% solution of sodium methoxide in methanol
g was injected once. The reaction was advanced by gradually heating. 7
Methanol started to distill from around 5 ° C, and foaming occurred around 85 ° C. The foaming was completed and the reaction was completed in about 30 minutes. After cooling, 2 l of water was added, and the mixture was extracted with 2 l of ethyl acetate. The aqueous layer was re-extracted with 2 l of ethyl acetate, and the ethyl acetate layers were combined and mixed with 3 l of water.
Washed twice with each. The ethyl acetate layer was concentrated under reduced pressure to give 250.3 g.
The title compound was obtained.

[Procedure Amendment 10]

[Document name to be amended] Statement

[Name of item to be corrected] 0029

[Correction method] Change

[Correction content]

[0029]
250.3 g of 2,4-dimethoxy-3,6-dimethylphenol obtained in (2) was dissolved in 2 l of acetone, 82.3 g of potassium hydroxide was added, and dimethylsulfate 16
6 g was added dropwise with stirring. The internal temperature rose from 20 ° C to 50 ° C and the reaction was completed in 30 minutes. Water 2 liters, dichloromethane 2 in the reaction mixture
1 was added and extracted. Dichloromethane layer 3 l of water 3 l
The extract was washed with water once and the dichloromethane layer was concentrated under reduced pressure. 236 g of crude product are obtained. 236 g of the crude product obtained are subjected to column chromatography on 1.2 kg of silica gel. n-hexane 5l, 5% isopropyl ether-n-hexane 4
l, 10% isopropyl ether-n-hexane (2 l) was eluted and the main fraction was concentrated to obtain 202 g of the title compound (yield: 85.6%). Oily substance.

[Procedure Amendment 11]

[Document name to be amended] Statement

[Name of item to be corrected] 0032

[Correction method] Change

[Correction content]

[0032]
1,3 -dimethyl- 2,5 -dimethoxybenzene

[Procedure Amendment 12]

[Document name to be amended] Statement

[Correction target item name] 0034

[Correction method] Change

[Correction content]

[0032]
Preparation of 2,6-dimethyl-4-Bro motor Fe <br/> Nord

[Procedure Amendment 13]

[Document name to be amended] Statement

[Correction target item name] 0036

[Correction method] Change

[Correction content]

[0036]
122 g of 2,6-dimethylphenol
Was dissolved in 1.2 l of chloroform. This was ice-cooled and 80 g of bromine was added dropwise over 40 minutes while maintaining the internal temperature at 10 to 20 ° C. to carry out the reaction. After completion of dropping, stirring was continued for 1 hour to complete the reaction. Add 10% sodium carbonate to the reaction mixture.
Extraction was performed by adding 1.2 liters of thorium water and 1.2 liters of chloroform. After separating chloroform, add 0.9 l of water to 2
After washing with water twice, the chloroform layer was concentrated under reduced pressure to obtain 205 g of a concentrated dry solid. And recrystallized by adding thereto n- hexane 1.5 l, 2,6-dimethyl-4-Bro motor Fe <br/> Nord 171.0 g (yield: 85.0%) was obtained.

[Procedure Amendment 14]

[Document name to be amended] Statement

[Correction target item name] 0039

[Correction method] Change

[Correction content]

[0039]
(1) obtained in 2,6-dimethyl-4-Bro mode phenol 171.0 g, copper iodide 32.
60 g of a mixture consisting of 3 g and 68.4 ml of dimethylfuran
The mixture was heated to 0 ° C., 655.9 g of a 28% methanol solution of sodium methoxide was injected at once, and gradually heated to advance the reaction. Methanol begins to distill at around 75 ° C, and 85
Foaming occurred at ° C. The foaming was completed in about 30 minutes, and the reaction was completed. After cooling, 1.4 l of water was added, and ethyl acetate 1.
It was re-extracted with 4 l, the ethyl acetate layers were combined and washed twice with 2.1 l water. Ethyl acetate was concentrated under reduced pressure to obtain 152.2 g of 2,6-dimethyl-4-methoxyphenol.

[Procedure Amendment 15]

[Document name to be amended] Statement

[Item name to be corrected] 0040

[Correction method] Change

[Correction content]

(3) Production of 1,3 -dimethyl- 2,5 -dimethoxybenzene

[Procedure 16]

[Document name to be amended] Statement

[Correction target item name] 0044

[Correction method] Change

[Correction content]

[0044]
126.9 g of the crude product obtained above were subjected to column chromatography on 635 g of silica gel. The main fraction was concentrated by eluting with 2.5 l of n-hexane, 2.0 l of 5% isopropyl ether-n-hexane and 1 l of 10% isopropyl ether-n-hexane.
107.9 g (yield: 85.0%) of the title compound was obtained.
Oily substance.

[Procedure Amendment 17]

[Document name to be amended] Statement

[Correction target item name] 0049

[Correction method] Change

[Correction content]

[0049]
(1) 2,3,5-Toriburo mode -p-
Cresol manufacture

[Procedure 18]

[Document name to be amended] Statement

[Correction target item name] 0054

[Correction method] Change

[Correction content]

282.8 g of 2,3,5- tribromo -p-cresol obtained in (1), 32.8 g of copper iodide,
A mixture of 113 ml of dimethyl furan was heated and 1990 g of a 28% solution of sodium methoxide in methanol were injected at once. The reaction was advanced by gradually heating. 75 ° C
Methanol started to distill from the position, and foaming occurred at about 85 ° C. Foaming is completed in about 30 minutes, the reaction was complete. After cooling, add 1.6 l of water and extract with 1.6 l of ethyl acetate.
It was The aqueous layer was re-extracted with 1.6 l of ethyl acetate, and the ethyl acetate layers were combined and washed twice with 2.4 l of water. Ethyl acetate was concentrated under reduced pressure, 142.9 g (yield: 100%) of the title compound.

[Procedure Amendment 19]

[Document name to be amended] Statement

[Correction target item name] 0057

[Correction method] Change

[Correction content]

[0057]
142.9 g of 2,3,5-trimethoxy-p-cresol obtained in (2) was mixed with 1.2 of acetone.
It was dissolved in 1 l, 48.2 g of potassium hydroxide was added, and 108.4 g of dimethyl sulfuric acid was added dropwise with stirring. Internal temperature from 20 ° C
Raised to 50 ° C. The reaction was completed in 30 minutes. 1.2 l of water and 1.2 l of dichloromethane were added to the reaction solution for extraction.
The dichloromethane layer was washed 3 times with 1.8 l of water, and the dichloromethane layer was concentrated under reduced pressure. 148.1 g of crude product are obtained.
148.1 g of the crude product obtained above is 740 g of silica gel.
Column chromatography. n-hexane 3
1.5% isopropyl ether-n-hexane 2.4
l, 10% isopropyl ether-n-hexane 1.2l
The main fraction was concentrated and eluted with 202 g of the title compound.
(Yield: 85.6%) was obtained. Oily substance.

[Procedure amendment 20]

[Document name to be amended] Statement

[Correction target item name] 0060

[Correction method] Change

[Correction content]

[0060]

[Reference Example] (E) -3- (2,3-dimethoxy-6-me
Tyl-1,4-benzoquinon-5-yl) -2-nonyl-2-propenoic acid

[Procedure correction 21]

[Document name to be amended] Statement

[Correction target item name] 0062

[Correction method] Change

[Correction content]

[0062]
(1) 2,3,6- tribromo -p-
Production of cresol (method of the present invention)

[Procedure correction 22]

[Document name to be amended] Statement

[Correction target item name] 0067

[Correction method] Change

[Correction content]

56,5.6 g of 2,3,6- tribromo -p-cresol obtained in (1), 65.6 g of copper iodide,
A mixture of 226 ml of dimethylfuran was heated and 3980 g of a 28% solution of sodium methoxide in methanol were injected at once. The reaction was advanced by gradually heating. 75 ° C
Methanol started to distill from the position and foaming occurred at 85 ° C. Foaming is completed in 45 minutes position, the reaction was complete. After cooling, 3.2 l of water was added and re-extracted with 3.2 l of ethyl acetate. The ethyl acetate layers were combined and washed twice with 4.8 l of water.
Ethyl acetate was concentrated under reduced pressure to yield 295.8 g (yield: 100
%) Of the title compound.

[Procedure amendment 23]

[Document name to be amended] Statement

[Name of item to be corrected] 0070

[Correction method] Change

[Correction content]

[0070]
2,3,6-trime obtained in (2)
285.8 g of toxy-p-cresol was added to acetone 2.4.
96.4 g of potassium hydroxide was added, and 216.8 g of dimethylsulfate was added dropwise with stirring. Internal temperature from 20 ° C
The temperature rose to 50 ° C and the reaction was completed in 30 minutes. Water in the reaction solution 2.
4 l and 2.4 l of dichloromethane were added and extracted. The dichloromethane layer was washed 3 times with 3.6 l of water, and the dichloromethane layer was concentrated under reduced pressure. 296.2 g of crude product are obtained.

148.1 g of the crude product obtained above was added to silica gel 740.
Subject to g column chromatography. n-hexane 3
1.5% isopropyl ether-n-hexane 2.4
l, 10% isopropyl ether-n-hexane 1.2l
The main fraction was concentrated and eluted with 202 g of the title compound.
(Yield: 85.6%) was obtained. Oily substance.

[Procedure amendment 24]

[Document name to be amended] Statement

[Correction target item name] 0073

[Correction method] Change

[Correction content]

[0073]
150.0 g of 2,3,4,5-tetramethoxytoluene obtained in (3) and 1.8 l of trifluoroacetic acid (TFA) were mixed and uniformly dissolved, and then hexamethylenetetramine was added with stirring to give 80 Heated to ~ 90 ° C. A heating reflux reaction was performed for 2 hours. Then, trifluoroacetic acid was distilled off by heating at atmospheric pressure. During distillation, the internal temperature is 8
The temperature gradually increased from 5 ° C., and when it reached 110 ° C., distillation was completed (distilled amount 900 ml). After cooling the concentrate, 4 l of water
Dissolved in water, and the pH was adjusted to 8 with 577.6 g of anhydrous sodium carbonate.
Made basic to a degree. Then, it was extracted with 2 l of ethyl acetate, the aqueous layer was re-extracted with 1 l of ethyl acetate, the ethyl acetate layers were combined, dried over anhydrous magnesium sulfate, and the solvent was depressurized.
Was evaporated, the crude product of the title compound 177.1g (yield:
104%).

[Procedure Amendment 25]

[Document name to be amended] Statement

[Correction target item name] 0074

[Correction method] Change

[Correction content]

[0074]
(5) (E) -3- [5- (6-methyl-1,2,3,4-trimethoxy) phenyl] -2
-Production of ethyl nonyl-2-propenoate

[Procedure Amendment 26]

[Document name to be amended] Statement

[Correction target item name] 0076

[Correction method] Change

[Correction content]

[0076]
6-methyl-2 obtained in (4),
3,4,5-Tetramethoxybenzaldehyde 177.
1 g, ethyl 2-diethylphosphonodecanenoate 38
A 28% sodium methoxide methanol solution is added dropwise to a mixed solution of 7.9 g and toluene 1.8 l. Internal temperature is 10 ° C
The rank has risen. Then stirred and heated to 55~60 ℃ position. After reacting for about 3.5 hours, it was cooled. 1.8 l of isopropyl ether and 0.3 l of diethyl ether were added, and the mixture was washed with 3.6 l of water. The organic layer is separated and washed with water, and anhydrous sulfuric acid is added.
After drying over magnesium, the solvent is concentrated under reduced pressure and the title compound is combined.
A crude product of the product was obtained.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Tomio Tsurugi 1-1044-130 Toyosatodai, Choshi-shi, Chiba (72) Inventor Hirofumi Kuroda 2-27-7 Onohara, Kamisu-cho, Kashima-gun, Ibaraki

Claims (6)

[Claims] 1. A compound represented by the general formula (I): (.R ² which means wherein R ^1, R ^3, R ⁴ is or different methyl or methoxy group is a hydrogen atom, a methyl group or a methoxy group. In the case R ³ is not a methoxy radical, R ²
And R ⁴ must be a methoxy group. ) P
-In the production of the dimethoxybenzene derivative, the compound of the general formula (II): (In the formula, R ¹ , R ³ and R ⁴ represent the same or different methyl groups or methoxy groups. R ² represents a hydrogen atom, a methyl group or a methoxy group, and when R ³ is not a methoxy group, A method for producing a p-dimethoxybenzene derivative, which comprises reacting a compound represented by R ² and R ⁴ with a methoxy group with dimethylsulfate. 2. A compound represented by the general formula (I): (In the formula, R ¹ , R ³ and R ⁴ represent the same or different methyl groups or methoxy groups. R ² represents a hydrogen atom, a methyl group or a methoxy group, and when R ³ is not a methoxy group, R ² and R ⁴ must be a methoxy group.) When producing a p-dimethoxybenzene derivative represented by
General formula (III) (Wherein R ¹ _a , R ³ _a and R ⁴ _a represent the same or different methyl groups or bromine atoms. R ² _a represents a hydrogen atom, a bromine atom or a methyl group) Was reacted with sodium methoxide to obtain the general formula (II) (In the formula, R ¹ , R ³ and R ⁴ represent the same or different methyl groups or methoxy groups. R ² represents a hydrogen atom, a methyl group or a methoxy group, and when R ³ is not a methoxy group, A method for producing a p-dimethoxybenzene derivative, which comprises reacting a compound represented by R ² and R ⁴ with a methoxy group with dimethylsulfate. 3. A compound represented by the general formula (I): (In the formula, R ¹ , R ³ and R ⁴ represent the same or different methyl groups or methoxy groups. R ² represents a hydrogen atom, a methyl group or a methoxy group, and when R ³ is not a methoxy group, R ² and R ⁴ must be a methoxy group.) When producing a p-dimethoxybenzene derivative represented by
General formula (IV): (Wherein R ¹ _b , R ² _b , R ³ _b and R ⁴ _b each independently represent a hydrogen atom or a methyl group.) The compound of the general formula (III ) [Chemical 8] (In the formula, R ¹ _a , R ³ _a , and R ⁴ _a represent the same or different methyl groups or bromine atoms. R ² _a represents a hydrogen atom, a bromine atom, or a methyl group. Further, R ³ _a represents bromine. When not an atom,
Both R ² _a and R ⁴ _a must be bromine atoms. ) Is reacted with sodium methoxide to obtain the compound of the general formula (II) (.R ² which means wherein R ^1, R ^3, R ⁴ is or different methyl or methoxy group is a hydrogen atom, a methyl group or a methoxy group. In the case R ³ is not a methoxy radical, R ²
And R ⁴ must be a methoxy group. ) 4. When 2,6-dimethyl-1,4-dimethoxybenzene is produced, 2,6-dimethylphenol is brominated with bromine. The obtained 4-bromo-2,
2,6-dimethyl-4-methoxyphenol is obtained by reacting 6-dimethylphenol with sodium methoxide, and the obtained 2,6-dimethyl-4-methoxyphenol is reacted with dimethylsulfate to give 2,6-dimethylphenol. A method for producing a p-dimethoxybenzene derivative according to claim 3, wherein -dimethyl-1,4-dimethoxybenzene is produced. 5. When producing 1,4-dimethyl-2,3,5-trimethoxybenzene, 2,4-dimethylphenol is brominated with a bromine atom to obtain 2,4.
-Dibromo-3,6-dimethylphenol was obtained, and the obtained 3,6-dimethyl-2,4-dimethoxyphenol was reacted with dimethylsulfate to give 1,4-dimethyl-
The method for producing a p-dimethoxybenzene derivative according to claim 3, wherein 2,3,5-trimethoxybenzene is produced. 6. When 2,3,4,5-tetramethoxytoluene is produced, p-cresol is brominated with bromine, and the obtained 2,3,6-tribromo-p-cresol is reacted with sodium methoxide. Let me 4-methyl-
2,3,6-trimethoxyphenol is obtained, and the obtained 4-methyl-2,3,6-trimethoxyphenol is reacted with dimethyl sulfate to produce 2,3,4,5-tetramethoxytoluene. The method for producing a p-dimethoxybenzene derivative according to claim 3, wherein [0001]