JPH115756A - Production of 2-alkyl azulene - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially advantageously obtain the subject compound useful as medicine, raw material for a legand of catalyst, and so on, by obtaining an azulene intermediate by the reaction of a cycloheptafuranone derivative with an active methyl and the like, followed by hydrolysis and decarboxylation without isolating the intermediate from the reaction products. SOLUTION: This compound shown by formula III is obtained by hydrolysis and decarboxylation of an azulene intermediate shown by formula II [R<7> and R<8> are each cyano, carboxyl, an alkoxycarbonyl, etc.], obtained by the reaction of one mole of a cyclohepta[b]furan-one derivative shown by formula I [R<1> is a (substituted) aliphatic or aromatic hydrocarbon; R<2> -R<6> are each H, a halogen, or an aliphatic or aromatic hydrocarbon, etc.] with about two moles of a compound having an active methyl or methylene (e.g. cyanoacetic acid ester, malonic acid diester, etc.) at room temperature to 40 deg.C for 1the 5 hours, without isolating the intermediate from the reaction products.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing 2-alkylazulene. Specifically, the present invention relates to a method for industrially and advantageously producing 2-alkylazulene from a cyclohepta [b] furan-2-one derivative. The 2-alkylazulene is useful as a drug, a raw material for a catalyst ligand, an electrophotographic photoreceptor, a liquid crystal device, an organic conductor, a cosmetic, a dye, and the like.

[0002]

2. Description of the Related Art Azulene derivatives have long been known as components of sagebrush and chamomile essential oil, which have been medicated in the private sector for a long time, but recently, anti-inflammatory agents, therapeutic agents for hyperlipidemia,
In addition to use as pharmaceuticals such as anticancer agents, electrophotographic photoreceptors,
It is a compound that is also attracting attention for use as a liquid crystal element, an organic conductor, cosmetics, a dye, and the like. Among them, azulene having a substituted alkyl group at the 2-position is an important basic compound,
There is a need for a manufacturing method that is easy and suitable for industrial production.

[0003] 2-alkylazulene which is one of 2-alkylazulene
As a method for synthesizing methylazulene, for example, 1-carboxy-3-cyano (or ethoxycarbonyl) -2-methylazulene is heated with sulfuric acid or the like to form 2-azulene.
A method for synthesizing methylazulene (tetrahedron (Te
(trahedron), 27, 3357 (1971))
It has been known.

[0004]

However, as a result of the inventor's additional testing of the method described in this document,
When 1-carboxy-3-cyano (or ethoxycarbonyl) -2-methylazulene is taken out, it is found that filtration is difficult due to the very fine crystals formed, and this method is carried out on an industrial scale. Doing has proven to be very disadvantageous in terms of operability and economy. An object of the present invention is to provide a method by which 2-alkylazulene can be industrially advantageously produced.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, have omitted the filtration operation, which is problematic, and continued hydrolysis and isolation without isolating the azulene intermediate. It has been found that by performing a decarboxylation reaction, 2-alkylazulene can be obtained in good yield, and the present invention has been completed. That is, the gist of the present invention is represented by the following formula (1)

[0006]

Embedded image

(Where R¹Has a substituent
Represents an aliphatic or aromatic hydrocarbon group which may be^TwoWhat
Chair R⁶Are each independently a hydrogen atom, a halogen atom
Or an aliphatic group which may have a substituent
Represents an aromatic hydrocarbon group; ^TwoOr R⁶Any of
May combine with each other to form a ring).
From the futa [b] furan-2-one derivative, the following formula (2)

[0008]

Embedded image

Wherein R ¹ to R ⁶ are as defined in the formula (1), and R ⁷ and R ⁸ are each independently a cyano group, a carboxyl group, an alkoxycarbonyl group, an alkanoyl group or an amide group Azulene intermediate represented by the following formula (3):

[0010]

Embedded image

(Wherein R ¹ to R ⁶ have the same meanings as in formula (1)). In a process for producing a 2-alkylazulene represented by formula (1), a compound of formula (1) is reacted with an active methyl or methylene group. A method for producing a 2-alkylazulene, wherein the compound of the formula (2) obtained by the reaction with the compound having the compound is continuously subjected to a hydrolysis reaction and a decarboxylation reaction without isolation from the reaction product solution; It is in. Hereinafter, the present invention will be described in detail.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION

(Condensation reaction) In the present invention, an azulene intermediate is first produced by reacting a cyclohepta [b] furan-2-one derivative with a compound having an active methyl or methylene group. This cyclohepta [b] furan-2-one derivative is, for example, tetrahedron (Tetraheon).
dron), 27, 3357 or 6023 (1971)
For example, in a solvent such as alcohol, a tropone derivative such as 2-chlorotropone, 2-methoxytropone or 2-arenesulfonyloxytropone, and an acetoacetate ester or a 3-oxybutanoate ester By reacting in the presence of a strong base such as sodium alkoxide or tert-butylamine. The cyclohepta [b] furan-2-one derivative used as a raw material in the present invention is specifically represented by the following formula (1)

[0013]

Embedded image

(Wherein, R ¹ is an aliphatic or aromatic hydrocarbon group which may have a substituent, R ² to R
⁶ each independently represents a hydrogen atom, a halogen atom or an aliphatic or aromatic hydrocarbon group which may have a substituent, and any of R ² to R ⁶ is bonded to form a ring May be used).

Specific examples of R ¹ in the formula (1) include those having 1 to 5 carbon atoms such as methyl, ethyl and isopropyl.
Lower alkyl groups, lower haloalkyl groups such as trifluoromethyl groups, phenyl groups, p-tolyl groups, (halo) aryl groups such as p-fluorophenyl groups, and the like.
Specific examples of R ² to R ⁶ include those having 1 carbon atom such as a hydrogen atom, a halogen atom, a methyl group, an ethyl group, and an isopropyl group.
About 5 lower alkyl groups, trifluoromethyl groups, substituted lower alkyl groups such as methoxymethyl groups,
Examples include a substituted aryl group such as a phenyl group, a p-chlorophenyl group, and a p-tolyl group, and the substituents of R ^{2 to} R ⁶ may be combined with each other to form a cyclic substituent. Examples of the compound having an active methyl or methylene group include cyanoacetate, malonate diester, acetoacetate, and malonamide.

In the condensation reaction, 1 to 5 moles, particularly about 2 moles, of the active methyl or methylene compound is usually charged in a solvent such as an alcohol such as ethanol with respect to 1 mole of the compound of the formula (1). The reaction is usually carried out in the presence of a metal alkoxide such as sodium ethoxide at room temperature to 60 ° C, preferably at room temperature to 40 ° C. The reaction time varies depending on the conditions.
About 5 hours.

(Hydrolysis / Decarboxylation Reaction) Next, the azulene intermediate obtained by this condensation reaction is hydrolyzed and decarboxylated to produce 2-alkylazulene.
In this case, in the conventional method, after mixing the reaction product liquid with water, the remaining raw materials and by-products are extracted and removed with an organic solvent such as chloroform, and then the resulting aqueous layer is acidified to azulene intermediate. The product is precipitated, filtered, washed, and dried to obtain a high-purity azulene intermediate, which is subjected to the next hydrolysis and decarboxylation reaction. However, in this method, it is very difficult to filter the crystals of the azulene intermediate obtained as described above.

On the other hand, the present invention is characterized in that the azulene intermediate is successively subjected to the next hydrolysis / decarboxylation reaction without isolation from the reaction product solution. That is, after mixing the reaction product solution with water, the alcohol component in the solution is removed by a method such as distillation without separating and removing the remaining raw materials and by-products to obtain an aqueous solution of an azulene intermediate. Subsequently, this aqueous solution is mixed with concentrated sulfuric acid or the like to make it acidic, and the precipitated azulene intermediate is subjected to a subsequent hydrolysis and decarboxylation reaction in a suspended state without being separated by filtration or the like. In this case, "without isolation" means that, unlike the conventional method, the produced azulene intermediate is not separated from the mother liquor, and therefore, the reaction product liquid remains, and some crystals of the intermediate are precipitated. However, this does not mean that it is separated, and that it remains as it is.

The subsequent hydrolysis and decarboxylation reaction is carried out by heating the resulting sulfuric acid suspension of the azulene intermediate to give 2-alkylazulene represented by the general formula (3) in high yield. Can be obtained at The amount of sulfuric acid used here may be any amount that can effectively agitate the reaction solution in a suspended state, and is usually 2 to 10 with respect to the azulene intermediate.
The molar amount is preferably 0 to 20 times, preferably 5 to 20 times from the viewpoint of economy and the like. The concentration of sulfuric acid used is 35
The reaction can be carried out at a low concentration or at a high concentration, where the reaction rate is low or the desired 2-
Since the selectivity of the alkylazulene is not sufficient, the reaction is preferably performed in the range of 45 to 75% by weight. Further, a method of adding concentrated sulfuric acid or the like during the reaction to change the concentration of sulfuric acid may be combined.

The reaction temperature is usually in the range of 70 to 140 ° C. If the temperature is lower than this, the reaction is slow and the selectivity of the target 2-alkylazulene is not sufficient, and if the temperature is higher than this, decomposition of the 2-alkylazulene occurs, which is not preferable. A method of gradually raising the temperature in consideration of the progress of the reaction, for example, the first step 7
0 to 105 ° C, preferably 80 to 100 ° C, second stage 11
A method of setting the temperature to 0 to 140 ° C. may be used.

The reaction time varies depending on conditions, but is usually about 0.5 to 10 hours. Separation and purification of the 2-alkylazulene obtained by the reaction can be performed by any conventional separation and purification method, but can be simply performed by extraction. That is, the reaction solution is left as it is, or after the reaction solution is brought into contact with water, extracted with an organic solvent such as chloroform, and the obtained extract of 2-alkylazulene is washed with water and the solvent is distilled off. -Alkyl azulene can be obtained. The obtained 2-alkylazulene can be further purified, if necessary, by a method such as distillation, sublimation, recrystallization, reprecipitation or column chromatography.

[0022]

Next, the present invention will be described in detail with reference to examples. However, the present invention is not limited to the examples unless it exceeds the gist. Example 1 1.50 g of 3-acetyl-2H-cyclohepta [b] furan-2-one (7.97 m) was placed in a 50 ml eggplant flask.
mol), 1.80 g of ethyl cyanoacetate (15.94 m
mol) and 4.50 ml of dry ethanol.
To this solution, 23.9 ml (23.9 mmol) of a 1N sodium ethoxide ethanol solution was added dropwise at room temperature over about 30 minutes. After the completion of the dropwise addition, the reaction was carried out at room temperature for about 6 hours.
7.75 ml of water was added to the reaction solution to make a homogeneous solution, and then ethanol was distilled off at normal pressure. Subsequently, concentrated sulfuric acid15.
7 g was added and reacted at about 80 ° C. for about 1 hour. Subsequently, the temperature of the reaction solution was raised to about 120 ° C., and the reaction was further performed for about 2 hours. After adding 15 ml of water to the reaction solution, the mixture was extracted twice with 15 ml of chloroform. The obtained organic layer was washed twice with 15 ml of water, and then the solvent was distilled off to obtain a blue-violet solid. This solid was obtained by HPLC and NM
As a result of analysis by R spectroscopy, it was 2-methylazulene. 0.91 g, 80% purity, 64% yield. From this result, it can be seen that the desired 2-alkylazulene was obtained in high purity and high yield without isolating the azulene intermediate which was difficult to filter on the way.

[0023]

According to the present invention, the filtration operation of the azulene intermediate, which is disadvantageous from an industrial point of view, is omitted, and a 2-alkyl-alkyl derivative of cyclohepta [b] furan-2-one is obtained in an industrially advantageous manner. Azulene can be produced.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Takeshi Ken Uegami 1-1 Kurosaki Castle Stone, Yawatanishi-ku, Kitakyushu City Inside Mitsubishi Chemical Corporation Kurosaki Office

Claims (4)

[Claims] [Claim 1] The following formula (1)(Where R¹Are fats each having a substituent
Represents an aliphatic or aromatic hydrocarbon group;^TwoOr R⁶Is
Each independently represents a hydrogen atom, a halogen atom or each
Aliphatic or aromatic carbons which may have a substituent
R represents a hydrogen group; ^TwoOr R⁶Is bonded to a ring
May be formed).
From the run-2-one derivative, the following formula (2)(Where R¹Or R⁶Has the same meaning as in formula (1),
⁷And R⁸Are each independently a cyano group,
A sil group, an alkoxycarbonyl group, an alkanoyl group or
An azulene intermediate represented by the following formula:
Then, the following formula (3)(Where R¹Or R⁶Is synonymous with equation (1))
The method for producing the represented 2-alkylazulene
And reacting the compound of formula (1) with an active methyl or methylene group
Compound of formula (2) obtained by reaction with compound having
Hydrolysis without isolation from the reaction product
2-Al which is subjected to a reaction and a decarboxylation reaction
Method for producing killazulene. ^2. The method according to claim 1, wherein R ² to R ⁶ are hydrogen atoms. 3. The method according to claim 1, wherein R ⁷ and R ⁸ are each independently a cyano group, a carboxyl group or an alkoxycarbonyl group. 4. The method according to claim 1, wherein R ¹ is a methyl group.