JP2002226473A - Method for manufacturing chroman carboxylic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for manufacturing a chroman carboxylic acid simply smoothly in high yield in high productivity on an industrial scale by using an easily available raw material or a less expensive raw material. SOLUTION: The method for manufacturing a chroman carboxylic acid comprises the following four processes: a dialkylphenol compound is made to react with a formaldehyde and an alcohol in the presence of a secondary amine and an acid to obtain an alkoxymethylated phenol compound (the first process), the obtained phenol compound is made to react with an ester having a carbon-carbon double bond at >=100 deg.C to obtain a dialkylchroman carboxylic acid ester (the second process), the obtained ester is subjected to hydrolysis to obtain a dialkylchroman carboxylic acid (the third process), (and the obtained carboxylic acid is allowed to react with an aromatic hydrocarbon in the presence of a Lewis acid (the fourth process).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a process for producing chromancarboxylic acid and a novel intermediate useful for the synthesis of chromancarboxylic acid. Chromanecarboxylic acid, for example,
Raw materials for pharmaceuticals showing β ₃ -adrenoceptor activity (W
O99 / 32475), useful as a raw material for a drug having an α ₂ -antagonistic action (see JP-A-59-130286), a synthetic raw material for a bactericide (see JP-A-61-291584), and the like. is there.

[0002]

2. Description of the Related Art Conventionally, as a method for producing chromancarboxylic acid, a method of obtaining 4-oxochromenecarboxylic acid from diethyl oxalate and 2-hydroxyacetophenone, and then hydrogenating the 4-oxochromenecarboxylic acid [ JP-A-59-130286], a method of obtaining phenoxylactone from bromobutyrolactone and phenol, and then reducing the phenoxylactone [Journal
Of Medicinal Chemistry (Journal
of Medical Chemistry), 14
Vol. 758-766 (1971)].

Japanese Patent Application Laid-Open No. 11-80147 discloses a process for obtaining an alkoxymethylated phenol compound by reacting a phenol compound, formaldehyde or alcohol in which at least one ortho position to a phenolic hydroxyl group is not substituted. The obtained alkoxymethylated phenol compound is converted into a hydroxyl group having a carbon-carbon double bond and an electron-withdrawing group directly bonded to a carbon atom constituting the carbon-carbon double bond in the molecule. A method of producing a chroman compound comprising a step of reacting the compound with a compound having no carbon-containing compound.
The reaction with esters having a carbon double bond has been intentionally excluded, and no dialkylchroman carboxylate has been obtained.

[0004]

The above-mentioned method not only involves the use of large amounts of acids and bases, but also involves the use of toxic oxalates, and the method uses expensive bromobutyrolactone. All of these methods are not industrially advantageous.

[0005] It is an object of the present invention to convert chromancarboxylic acid to
Using easily available raw materials and inexpensive raw materials, in high yield,
It is an object of the present invention to provide a method for easily and smoothly producing a product industrially with good productivity.

[0006]

Means for Solving the Problems The present inventors have studied to achieve the above object. By reacting an easily available and inexpensive dialkylphenol compound, formaldehydes and alcohol in the presence of a secondary amine and an acid, an alkoxymethylated phenol compound in which the ortho position to the phenolic hydroxyl group is alkoxymethylated is obtained. The obtained alkylmethylated phenol compound is reacted with an ester having a carbon-carbon double bond at a temperature of 100 ° C. or higher to obtain a dialkylchromancarboxylic acid ester (second step). Step), dialkyl chroman carboxylic acid ester obtained is hydrolyzed to obtain dialkyl chroman carboxylic acid (third step), and the obtained dialkyl chroman carboxylic acid is reacted with an aromatic hydrocarbon in the presence of a Lewis acid. (4th step) It found that a carboxylic acid can be produced smoothly at high yield.

Further, the present inventors have proposed that the reaction of the alkoxymethylated phenol compound and the ester having a carbon-carbon double bond is carried out in the second step in the presence of an acid to accelerate the reaction. Was found to be possible.

Further, the present inventors have found that a specific synthetic intermediate in the process for producing chromancarboxylic acid comprising the above four reaction steps is a novel compound.

That is, the present invention provides a compound represented by the general formula (I)

[0010]

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(Wherein, R ¹ and R ² each independently represent an alkyl group, and R ³ represents a hydrogen atom or an alkyl group) [hereinafter referred to as dialkyl chroman carboxylic acid (I)
Is reacted with an aromatic hydrocarbon in the presence of a Lewis acid.

[0012]

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(Wherein R ³ is as defined above) [hereinafter referred to as chromancarboxylic acid (II)].

Further, the present invention provides a compound represented by the following general formula (III):

[0015]

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(Wherein R ¹ and R ² are as defined above) [hereinafter referred to as dialkylphenol compound (III)
), Formaldehydes and alcohols
The reaction is carried out in the presence of a secondary amine and an acid to obtain a compound of the formula (I)
V)

[0017]

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(Wherein R ¹ and R ² are as defined above, and R ⁴ represents an alkoxyl group) [hereinafter referred to as alkoxymethylated phenol compound (IV) (The first step), and the obtained alkoxymethylated phenol compound (IV) is represented by the general formula (V)

[0019]

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(Wherein, R ³ is as defined above, and R ⁵ represents an alkyl group or an aralkyl group.)
Esters having a carbon-carbon double bond [hereinafter referred to as unsaturated esters (V)] and 100
The reaction is carried out at a temperature of at least

[0021]

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Wherein R ¹ , R ² , R ³ and R ⁵
Is as defined above. (Hereinafter referred to as dialkylchromancarboxylic acid ester (VI)) (second step), and the resulting dialkylchromancarboxylic acid ester (VI) is hydrolyzed. A dialkylchromancarboxylic acid (I) is obtained (third step), and the obtained dialkylchromancarboxylic acid (I) is reacted with an aromatic hydrocarbon in the presence of a Lewis acid (fourth step). This is a method for producing chromancarboxylic acid (II).

The present invention further relates to a dialkyl chroman carboxylic acid (I) and an alkoxymethylated phenol compound (IV).

The present invention also provides an alkoxymethylated phenol compound (IV) by reacting a dialkylphenol compound (III), formaldehydes and an alcohol in the presence of a secondary amine and an acid. The methylated phenol compound (IV) is reacted with the unsaturated esters (V) at a temperature of 100 ° C. or higher to obtain a dialkyl chroman carboxylate (VI), and the obtained dialkyl chroman carboxylate (VI)
And a method for producing a dialkylchromancarboxylic acid (I).

[0025]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula, R¹ , R² , R
³ And R⁵ Is an alkyl group represented by
A linear or branched alkyl group having a prime number of 1 to 8 is preferable,
For example, methyl group, ethyl group, propyl group, isopropyl
Group, butyl group, isobutyl group, t-butyl group, hexyl
Group, 2-ethylhexyl group, octyl group and the like.
You. R ⁴ As the alkoxyl group represented by
And an alkoxyl group such as methoxy,
Toxyl group, 1-propoxy group, 1-butoxy group, 1-he
Xanoxy group, 1-octanoxy group, 2-ethyl-1-
Hexanoxy group, 2-propoxy group, 2-butoxy group,
Cyclohexanoxy group, 2-hydroxy-1-ethoxy
Group, 4-hydroxy-1-butoxy group, 6-hydroxy
-1-hexanoxy group, benzyloxy group, phenethyl
Oxy groups and the like can be mentioned. R⁵ Aralkyl group represented by
The aryl moiety has 6 to 14 carbon atoms and
Aralkyl groups having 1 to 6 carbon atoms in the alkyl moiety are preferred.
And examples thereof include a benzyl group and a phenethyl group.
You.

In the first step, the dialkylphenol compound (III), formaldehydes and alcohol are reacted in the presence of a secondary amine and an acid to obtain an alkoxymethylated phenol compound (IV). This alkoxymethylated phenol compound (IV) is novel and is provided for the first time by the present invention.

Examples of the formaldehyde include linear polymers of formalin such as formalin and paraformaldehyde; and cyclic acetal oligomers such as trioxane and tetraoxane. These formaldehydes may be used alone or in combination of two or more.

Examples of the alcohol include methanol, ethanol, 1-propanol, 1-butanol,
1-hexanol, 1-octanol, 2-ethyl-1
A saturated aliphatic primary alcohol such as hexanol; 2
-Saturated aliphatic secondary alcohols such as propanol, 2-butanol and cyclohexanol; saturated aliphatic diols such as ethylene glycol, 1,4-butanediol and hexylene diol; aralkyl alcohols such as benzyl alcohol and phenethyl alcohol. No. These alcohols may be used alone or in combination of two or more. The above general formula (I
The alkoxyl group R ⁴ in V) is derived from the above-mentioned alcohol.

The above-mentioned secondary amine and acid act as a catalyst and / or a reaction accelerator for producing the alkoxymethylated phenol compound (IV).

As the secondary amine, any of an aliphatic secondary amine and an aromatic secondary amine can be used. The type of the secondary amine is not particularly limited.
Dibutylamine, bis (2-ethylhexyl) amine,
Linear aliphatic secondary amines such as dioctylamine; cyclic aliphatic secondary amines such as piperidine, pyrrolidine and morpholine
Secondary amine; and aromatic secondary amines such as N-methylaniline and N-ethylaniline. These secondary amines may be used alone or in combination of two or more.

As the acid, any of an organic acid and an inorganic acid can be used, but it is preferable to use an organic acid from the viewpoint of selectivity. Among them, a saturated fatty acid having 2 to 8 carbon atoms and an aromatic fatty acid are preferably used. preferable. Examples of such organic acids include acetic acid, propionic acid, butyric acid, 2-methylpropanoic acid, valeric acid, 3-methylbutanoic acid, 2-methylbutanoic acid, hexanoic acid, heptanoic acid, octanoic acid, and benzoic acid. These acids may be used alone or in combination of two or more.

In the reaction of the first step, the formaldehyde is used in an amount of 0.1 to 1 equivalent of the dialkylphenol compound (III) so that the formation of the alkoxymethylated phenol compound (IV) can be carried out smoothly. 8-10
The range of equivalents is preferable, and the range of 1 to 2 equivalents is more preferable. The amount of alcohol used is preferably in the range of 0.8 to 20 equivalents, more preferably in the range of 1 to 10 equivalents. The use amount of the secondary amine is preferably in the range of 0.001 to 1 equivalent,
A range of 0.01 to 0.5 equivalent is more preferred. The amount of the acid used is preferably in the range of 0.01 to 5 equivalents, and 0.1 to 1.
A range of 0 equivalents is more preferred.

The reaction of the first step can be carried out in the presence or absence of a solvent. As the solvent, for example, an inert solvent such as toluene, xylene, or N-methylpyrrolidone is used. The amount of the solvent used is 50 to 1000 parts by weight based on 100 parts by weight of the dialkylphenol compound (III).
A range of parts by weight is preferred.

The reaction of the first step is performed by reacting a dialkylphenol compound (III), formaldehydes, alcohol,
It is carried out by mixing a secondary amine, an acid and, if necessary, a solvent. The reaction temperature is preferably in the range of 50 to 150C, more preferably in the range of 80 to 120C. When the boiling point of the alcohol used is lower than the above-mentioned reaction temperature, the reaction is preferably performed under pressurized conditions. The reaction time varies depending on the type of the dialkylphenol compound (III), formaldehydes, alcohol, secondary amine and acid used, but is preferably in the range of 30 minutes to 24 hours.

In the reaction of the first step, water is produced as a by-product. By removing this water from the reaction system during the reaction, the reaction time can be shortened.

In the second step, the alkoxyalkylated phenol compound (IV) obtained in the first step is reacted with the unsaturated ester (V) at a temperature of 100 ° C. or more to convert the dialkylchromancarboxylic acid ester (VI). obtain.

The alkoxymethylated phenolic compound (IV) obtained in the first step may be used in the second step without isolation from the reaction system, but the dialkylchromancarboxylic acid ester (VI) can be obtained in a high yield. In order to obtain the compound at a high rate, it is preferable to isolate the produced alkoxymethylated phenol compound (IV) from the reaction system in the first step and to use it after performing a washing treatment or the like in some cases. In this case, the method for isolating the alkoxymethylated phenol compound (IV) from the reaction system in the first step includes adding a solvent such as an aromatic hydrocarbon such as toluene or xylene; or an ether such as diisopropyl ether to the reaction system. And a vacuum distillation method.

In the second step, one or more unsaturated esters (V) can be used. The amount of the unsaturated ester (V) used is such that the formation of the dialkylchromancarboxylic acid ester (VI) can be performed smoothly.
The range is preferably 0.8 to 20 equivalents, more preferably 1.0 to 10 equivalents, relative to the alkoxymethylated phenol compound (IV).

The reaction in the second step is preferably performed in the absence of a solvent, but may be performed in the presence. When the reaction is performed in the presence of a solvent, for example, an inert solvent such as decalin, mesitylene, or N-methylpyrrolidone is preferably used.
The amount of the solvent used is preferably in the range of 50 to 500 parts by weight based on 100 parts by weight of the alkoxymethylated phenol compound (IV).

The reaction in the second step is preferably carried out in the presence of an acid. The acid acts as a catalyst and / or a reaction accelerator for producing the dialkylchromancarboxylic acid ester (VI). As the acid, any of an organic acid and an inorganic acid can be used, but an organic acid is preferably used in terms of selectivity, and among them, a saturated fatty acid having 2 to 8 carbon atoms and an aromatic fatty acid are preferably used. Examples of such an acid include acetic acid, propionic acid, butyric acid, 2-methylpropanoic acid, valeric acid, 3-methylbutanoic acid, 2-methylbutanoic acid, hexanoic acid, heptanoic acid, octanoic acid, and benzoic acid. These acids may be used alone or in combination of two or more. The amount of the acid to be used is preferably in the range of 0.1 to 100 mol%, more preferably in the range of 1 to 10 mol%, based on the alkoxymethylated phenol compound (IV).

The reaction in the second step is carried out at a temperature of 100 ° C. or higher by mixing the alkoxymethylated phenol compound (IV), unsaturated esters (V), and, if necessary, an acid and a solvent. The reaction temperature is preferably in the range of 100 to 250C, more preferably in the range of 120 to 200C. When the boiling point of the unsaturated ester (V) used is lower than the above-mentioned reaction temperature, the reaction is preferably carried out under pressurized conditions.
The reaction time was determined using the alkoxymethylated phenol compound (I
Although it depends on the types of V) and unsaturated esters (V), it is preferably about 30 minutes to 48 hours.

In the second step, alcohol is generated as a by-product. By removing this alcohol from the reaction system during the reaction, the reaction time can be shortened.

In the third step, the dialkylchromancarboxylic acid (I) is obtained by hydrolyzing the dialkylchromancarboxylic acid ester (VI) obtained in the second step. This dialkylchromancarboxylic acid (I) is novel and is provided for the first time by the present invention.

The dialkylchroman carboxylate (VI) obtained in the second step may be used in the third step without isolation from the reaction system, but may be isolated from the reaction system in the second step, and may be optionally used. It is preferable to use it after performing a washing treatment or the like. As a method for isolating the dialkyl chroman carboxylate (VI) from the reaction system in the second step at that time, for example, a solvent such as an aromatic hydrocarbon such as toluene or xylene; or an ether such as diisopropyl ether may be added to the reaction system. And a method of performing distillation under reduced pressure, and a method of performing distillation under reduced pressure.

The hydrolysis in the third step is preferably carried out in the presence of an acid or a base, more preferably in the presence of a base.

The type of the acid is not particularly limited, and examples thereof include mineral acids such as hydrochloric acid and sulfuric acid; and organic acids such as p-toluenesulfonic acid. The amount of the acid to be used is preferably in the range of 0.1 to 10 moles per mole of the dialkylchromancarboxylic acid ester (VI).

The type of the base is not particularly limited, and examples thereof include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; and calcium hydroxide, magnesium hydroxide and barium hydroxide. Alkaline earth metal hydroxide and the like. The amount of the base used is dialkylchromancarboxylic acid ester (VI) 1
It is preferably in the range of 0.7 to 5 moles,
A range of モ ル 3 mol is more preferred.

In the third step, an alcohol can be added to the reaction system for the purpose of promptly proceeding the hydrolysis reaction. The type of the alcohol is not particularly limited, and examples thereof include methanol, ethanol, and alcohol.
-Propanol, 1-butanol, 1-hexanol,
Saturated aliphatic primary alcohols such as 1-octanol and 2-ethyl-1-hexanol; 2-propanol, 2
-Saturated aliphatic secondary alcohols such as butanol and cyclohexanol; and saturated aliphatic diols such as ethylene glycol, 1,4-butanediol and hexylene diol. The amount of the alcohol used is 0.5 to 0.5 parts by weight of the dialkylchromancarboxylic acid ester (VI).
A range of 10 times weight is preferable, and a range of 1.0 to 3 times weight is more preferable.

The reaction of the third step is carried out by mixing the dialkyl chroman carboxylate (VI), water, and, if necessary, an acid or a base and an alcohol. The reaction temperature is preferably in the range of 20 to 120C, and 50C to 10C.
A range of 0 ° C. is more preferred. When the reaction is performed at a temperature higher than the boiling point of the alcohol or water to be used, the reaction is preferably performed under pressurized conditions. The reaction time may vary depending on the type of the dialkyl chroman carboxylate (VI), but is preferably about 30 minutes to 48 hours.

In the fourth step, the dialkylchromancarboxylic acid (I) obtained in the third step is reacted with an aromatic hydrocarbon in the presence of a Lewis acid to obtain a chromancarboxylic acid (II).

The dialkylchromancarboxylic acid (I) is
It may be used in the next fourth step without isolation from the reaction system in the above third step, but it is preferable to use it after isolating it from the reaction system and optionally performing a washing treatment or the like. Examples of the isolation method include a method in which a solvent such as an aromatic hydrocarbon such as toluene and xylene; an ether such as diisopropyl ether is added to the reaction system to perform an extraction treatment, a method in which distillation is performed under reduced pressure, and the like. When the hydrolysis is performed in the presence of a base, it is preferable to remove impurities such as a polymer by dissolving the resulting dialkylchromancarboxylate in an aqueous layer and extracting the resultant with an organic solvent.

In the fourth step, the Lewis acid acts as a catalyst and / or a reaction accelerator for forming chromancarboxylic acid (II). As the Lewis acid, a metal chloride is preferably used, and the type thereof is not particularly limited, and examples thereof include aluminum chloride, zinc chloride, and iron chloride. These Lewis acids may be used alone or in combination of two or more.

The amount of the Lewis acid used is 0.1 to 5 with respect to 1 equivalent of the dialkylchromancarboxylic acid (I) so that the formation of the chromancarboxylic acid (II) can be carried out smoothly.
The range of equivalents is preferable, and the range of 0.5 to 2 equivalents is more preferable.

The kind of the aromatic hydrocarbon is not particularly limited. However, in order that the formation of chromancarboxylic acid (II) can be carried out smoothly, electron-donating substances such as toluene, xylene and cumene can be used. It is preferable to use an aromatic hydrocarbon having a substituent. These aromatic hydrocarbons may be used alone or in combination of two or more.

The amount of the aromatic hydrocarbon used is preferably as large as possible in order to smoothly produce the chromancarboxylic acid (II), but from the viewpoint of economy, the dialkylchromancarboxylic acid (I) is preferably used. 1 to 1 equivalent
A range of 100 equivalents is preferred, and a range of 2 to 50 equivalents is more preferred.

The reaction in the fourth step is preferably carried out in the absence of a solvent, but may be carried out in the presence. When the reaction is performed in the presence of a solvent, an inert solvent such as hexane and heptane is used. The amount of the solvent used is 50 to 100 parts by weight based on 100 parts by weight of the dialkylchromancarboxylic acid (I).
A range of 0 parts by weight is preferred.

The reaction of the fourth step is carried out by mixing dialkylchromancarboxylic acid (I), Lewis acid, aromatic hydrocarbon and, if necessary, a solvent. Reaction temperature is 0-2
The range of 00 ° C is preferred, and the range of 10 to 140 ° C is more preferred. When the aromatic hydrocarbon used has a boiling point lower than the above-mentioned reaction temperature, the reaction is preferably performed under pressurized conditions. The reaction time varies depending on the type of dialkylchromancarboxylic acid (I), but is preferably about 30 minutes to 48 hours.

The chromancarboxylic acid (II) produced by the above reaction can be isolated, if necessary, and can be purified by washing or crystallization as necessary. As a method for isolating chromancarboxylic acid (II), for example, a reaction system is prepared by adding an aromatic hydrocarbon such as toluene and xylene; a solvent such as ethers such as diisopropyl ether; water; and, if necessary, an acid or a base. A method of performing an extraction treatment, a method of performing distillation under reduced pressure, and the like are included.

[0059]

EXAMPLES The present invention will be described below in detail with reference to examples, but the present invention is not limited to these examples.

Example 1 Synthesis of 2,4-di-tert-butyl-6-butoxymethyl-1-hydroxybenzene 472.2 g of 2,4-di-tert-butylphenol (2.
29 mol), 87.3% paraformaldehyde 95.
1 g (2.77 mol), di-n-butylamine
6 g (0.229 mol), acetic acid 69.8 g (1.16 mol)
mol), 1183.1 g of 1-butanol (15.96)
mol) and 590 g of toluene.
The mixture was heated and stirred for 0 hours. On the way, generated water was removed. After the completion of the reaction, the reaction mixture was washed with a dilute aqueous sulfuric acid solution, a sodium hydrogen carbonate aqueous solution and water in that order, and the organic layer was concentrated. When the concentrated solution was quantitatively analyzed by an internal standard method using a liquid chromatograph, 2,4-di-t-butyl-6-butoxymethyl-1-hydroxybenzene was produced in a yield of 91%. The ¹ H-NMR data of the obtained 2,4-di-t-butyl-6-butoxymethyl-1-hydroxybenzene are shown below.

Δ ppm (CDCl ₃ , 300 MHz)
7.27 (1H, d), 6.88 (1H, d), 4.6
8 (2H, s), 3.57 (2H, t, J = 6.45H)
z), 1.5-1.8 (4H, m), 0.95 (3H,
t, J = 7.32 Hz), 1.44 (9H, s), 1.
30 (9H, s)

Example 2 Synthesis of 6,8-di-t-butyl-2-butoxycarbonylchroman 2,4-di-t-butyl-6-butoxymethyl-1-hydroxybenzene 665 obtained in Example 1 .2g [n
et586.71 g (2.01 mol)], 771.2 g (6.02 mol) of butyl acrylate and 12.26 g (0.10 mol) of benzoic acid were added.
The mixture was heated and stirred at 65 ° C. for 30 hours. Along the way, 1
-Butanol was removed. After the completion of the reaction, the reaction mixture was quantitatively analyzed by an internal standard method using a liquid chromatograph. ). Further, the regioisomer 6,8-di-t-
Butyl-3-butoxycarbonylchroman was produced in a yield of about 8%. For use in the next step, excess butyl acrylate was distilled off under reduced pressure, toluene was added to the residue, and benzoic acid was removed with an aqueous sodium hydrogen carbonate solution. The ¹ H-NMR data of the obtained 6,8-di-t-butyl-2-butoxycarbonylchroman is shown below.

Δ ppm (CDCl ₃ , 300 MHz)
7.18 (1H, d), 6.90 (1H, d), 4.6
8 (1H, dd, J = 3.48, J = 5.01);
18-4.22 (2H, m), 2.79-2.90 (2
H, m), 2.28 (1H, m), 2.18 (1H,
m), 1.60-1.70 (4H, m), 1.43 (9
H, s), 1.30 (9H, s), 0.92 (3H,
t, J = 7.41)

Example 3 Synthesis of 6,8-di-t-butyl-2-hydroxycarbonylchroman Toluene solution of 6,8-di-t-butyl-2-butoxycarbonylchroman obtained in Example 2 183. 0g
To [net 69.3 g (0.2 mol)], 120.0 g (0.3 mol) of a 10% aqueous sodium hydroxide solution and 120 g of methanol were added, and the mixture was heated with stirring at 70 ° C. for 2 hours. Toluene was added to the reaction mixture, and the mixture was stirred, allowed to stand, and methanol and the like were removed from the separated aqueous layer. After removal, an aqueous solution of sulfuric acid was added to the aqueous layer, extracted with toluene, and the extract was concentrated. When the concentrate was quantitatively analyzed by an internal standard method using a liquid chromatograph, 6,8-di-t was obtained.
98% of -butyl-2-hydroxycarbonylchroman
In a yield of 56.92 g (0.196 mol) of net. The resulting 6,8-di-t-butyl-2-
The ¹ H-NMR data of hydroxycarbonylchroman is shown below.

Δ ppm (CDCl ₃ , 300 MHz)
7.20 (1H, d), 6.93 (1H, d), 4.7
3 (1H, dd, J = 3.45, J = 5.19);
78-2.98 (2H, m), 2.29-2.41 (1
H, m), 2.12-2.28 (1H, m), 1.42
(9H, s), 1.29 (9H, m)

Example 4 Synthesis of 2-chromancarboxylic acid 2.90 g (0.01 mol) of 6,8-di-t-butyl-2-hydroxycarbonylchroman obtained in Example 3
l) was dissolved in 27 g of toluene, and the resulting solution was added dropwise to a suspension of 2.67 g (0.02 mol) of aluminum chloride in toluene at room temperature. After the dropwise addition, the mixture was stirred at room temperature for 2 hours, then, the reaction mixture was poured into a sulfuric acid aqueous solution, and the organic layer was separated. An aqueous alkali solution was added to the organic layer, and the aqueous layer was separated. An aqueous sulfuric acid solution was added to the aqueous layer, and extracted with toluene.
The extract was concentrated. When the concentrate was quantitatively analyzed by an internal standard method using a liquid chromatograph, the yield of 2-chromancarboxylic acid was 90% [net 1.60 g (0.001 g).
9 mol)]. The ¹ H-NMR data of the obtained 2-chromancarboxylic acid is shown below.

Δ ppm (CDCl ₃ , 300 MHz)
7.12 (2H, m), 6.92 (2H, m), 4.7
7 (1H, dd, J = 3.57, J = 4.38);
78-2.96 (2H, m), 2.32-2.42 (1
H, m), 2.17-2.27 (1H, m)

[0068]

According to the present invention, chromancarboxylic acid (II) can be obtained simply, smoothly and industrially with high productivity by using easily available raw materials and inexpensive raw materials. it can.

Continued on the front page F term (reference) 4C062 FF71 FF73 4H006 AA01 AA02 AB84 AC43 BA32 BA34 GN24 GP01 GP12 4H039 CA61 CD10 CD40

Claims (8)

[Claims] 1. A compound of the general formula (I) (Wherein, R ¹ and R ² each independently represent an alkyl group, and R ³ represents a hydrogen atom or an alkyl group.) Wherein the dialkylchroman carboxylic acid is represented by the formula: General formula (II) characterized by reacting (Wherein R ³ is as defined above). 2. A compound of the general formula (III) (Wherein, R ¹ and R ² each independently represent an alkyl group.)
Formaldehydes and alcohols are reacted in the presence of a secondary amine and an acid to form a compound of the general formula (IV) (Wherein R ¹ and R ² are as defined above,
R ⁴ represents an alkoxyl group. )), And the obtained alkoxymethylated phenol compound is represented by the general formula (V): (Wherein, R ³ represents a hydrogen atom or an alkyl group;
⁵ represents an alkyl group or an aralkyl group. ) And an ester having a carbon-carbon double bond and 100 ° C.
The reaction is carried out at the above temperature to obtain a compound of the general formula (VI) (Wherein R ¹ , R ² , R ³ and R ⁵ are as defined above), and the dialkyl chroman carboxylate obtained is hydrolyzed to obtain a dialkyl chroman carboxylate. Formula (I) Wherein R ¹ , R ² and R ³ are as defined above, and the obtained dialkyl chroman carboxylic acid is converted to an aromatic hydrocarbon in the presence of a Lewis acid. Having the general formula (II): (Wherein R ³ is as defined above). 3. An alkoxymethylated phenol compound represented by the general formula (IV) and a carbon-containing compound represented by the general formula (V):
The method according to claim 2, wherein the reaction of the ester having a carbon double bond is carried out in the presence of an acid. 4. A compound of the general formula (I) (Wherein, R ¹ and R ² each independently represent an alkyl group, and R ³ represents a hydrogen atom or an alkyl group). 5. In the general formula (I), R ¹ and R ² represent a t-butyl group, and R ³ represents a hydrogen atom.
The dialkyl chroman carboxylic acid according to the above. 6. A compound of the general formula (IV) (Wherein, R ¹ and R ² each independently represent an alkyl group, and R ⁴ represents an alkoxyl group). 7. The compound of the formula (IV) wherein R ¹ and R ²
Represents an t-butyl group. The alkoxymethylated phenol compound according to claim 6, wherein 8. A compound of the general formula (III) (Wherein, R ¹ and R ² each independently represent an alkyl group.)
Formaldehydes and alcohols are reacted in the presence of a secondary amine and an acid to form a compound of the general formula (IV) (Wherein R ¹ and R ² are as defined above,
R ⁴ represents an alkoxyl group. ) Is obtained, and the obtained alkoxymethylated phenol compound is represented by the general formula (V): (Wherein, R ³ represents a hydrogen atom or an alkyl group;
⁵ represents an alkyl group or an aralkyl group. ) And an ester having a carbon-carbon double bond and 100 ° C.
The reaction is carried out at the above temperature to obtain the compound represented by the general formula (VI). Wherein R ¹ , R ² , R ³ and R ⁵ are as defined above, and hydrolyzing the obtained dialkyl chroman carboxylate. General formula (I) (Wherein R ¹ , R ² and R ³ are as defined above).