HUP0103480A2 - Method for producing chroman-carboxylic acid - Google Patents

Abstract

The subject of the present invention is a process for the production of a chroman carboxylic acid, during which a dialkylphenol compound, a formaldehyde and an alcohol are reacted with each other in the presence of a secondary amine and an acid to obtain an alkoxymethylated phenol compound (step 1); the thus obtained alkoxymethylated phenol compound is reacted with an ester having a carbon-carbon double bond at a temperature not lower than 100°C to obtain a dialkylchromancarboxylic acid ester (step 2); the resulting dialkylchromancarboxylic acid ester is hydrolyzed to give a dialkylchromancarboxylic acid (step 3); and finally, the resulting dialkylchromanecarboxylic acid is reacted with an aromatic hydrocarbon in the presence of a Lewis acid (step 4). HE

Description

S.B.G. & K.

Nemzcikozi

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H-'(K>_ P i > ₍ I ' v I' IB.

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73.262/SZE publication copy

PROCEDURE FOR CHROMIC CARBONIC ACID

FOR PRODUCTION

The present invention relates to a process for the preparation of chromancarboxylic acid and to a novel intermediate for the synthesis of chromancarboxylic acid. Chromancarboxylic acid can be used, for example, as a starting material for pharmaceutical products exhibiting β-adrenergic receptor activity (see WO 99/32475), and as a starting material for pharmaceutical products exhibiting α2-antagonist activity (see EP 0 115 142) and a fungicide (see USP 4,745 114).

The following methods are traditionally known for the preparation of chromancarboxylic acid: 1) 4-oxochromenecarboxylic acid is prepared from diethyl oxalate and 2-hydroxyacetophenone, and then this 4-oxochromenecarboxylic acid is hydrogenated (see JP-A-59130286), or 2) phenoxylactone is prepared from bromobutyrolactone and phenol, and then the phenoxylactone is reduced [J. Med. Chem., 14: 758-766, (1971)]. Furthermore, EP 0 891 974 discloses a further process for preparing a chroman compound, which process comprises reacting a phenol compound (in which at least one ortho position to the phenolic hydroxy group is unsubstituted), a formaldehyde and an alcohol to obtain an alkoxymethylated phenol compound, and then reacting the thus obtained alkoxymethylated phenol compound with a compound containing a carbon-carbon double bond and in which no hydroxy group or an electron-withdrawing group is directly attached to the carbon atoms participating in the carbon-carbon double bond in the molecule.

However, the above-mentioned method 1) uses a large amount of acid and base, as well as toxic oxalic acid ester, and the method 2) uses expensive bromobutyrolactone. Neither of these methods is industrially advantageous.

The present invention therefore aims to provide a process by which chroman carboxylic acid can be easily and problem-freely prepared from readily available or economical starting materials in high yield and with high industrial productivity.

We have found that by reacting an easily available and economical dialkylphenol compound, a formaldehyde and an alcohol in the presence of a secondary amine and an acid, an alkoxymethylated phenol compound can be obtained, where the ortho position (relative to the phenolic hydroxy group) is alkoxymethylated (Step 1); by reacting the thus obtained alkoxymethylated phenol compound with an ester having a carbon-carbon double bond at a temperature not lower than 100°C, a dialkylchromancarboxylic acid ester can be obtained (Step 2); and by hydrolysis of the thus obtained dialkylchromancarboxylic acid ester, a dialkylchromancarboxylic acid can be obtained (Step 3);

and finally, if the thus obtained dialkylchromancarboxylic acid is reacted with an aromatic hydrocarbon in the presence of a Lewis acid, then the chromancarboxylic acid can be obtained without problems and in high yield (Step 4).

Furthermore, we have found that if the alkoxymethylated phenol compound is reacted with the ester having a carbon-carbon double bond in the presence of an acid (Step 2), the reaction can be accelerated.

We have further found that during the preparation of chroman carboxylic acid, which involves the above-mentioned 4 reaction steps, a certain intermediate is a novel compound.

That is, the present invention provides a process for preparing a chroman carboxylic acid of the general formula (II) -wherein R ³ represents a hydrogen atom or an alkyl group (the compound of the general formula (II) is hereinafter referred to as chroman carboxylic acid)-, which process comprises reacting a dialkyl chroman carboxylic acid of the general formula (I) -wherein R ¹ and R ² independently represent an alkyl group and R ³ is as defined above (the compound of the general formula (I) is hereinafter referred to as dialkyl chroman carboxylic acid)- with an aromatic hydrocarbon in the presence of a Lewis acid.

The present invention also provides a process for preparing a chroman carboxylic acid (II), which process comprises: reacting a dialkylphenol compound of the general formula (III) in the presence of a secondary amine and an acid

-wherein R ¹ and R ² are as defined above (the compound of general formula (III) is hereinafter referred to as a dialkylphenol compound)-, a formaldehyde and an alcohol are reacted with each other to obtain an alkoxymethylated phenol compound of general formula (IV) where R ¹ and R ² are as defined above and R ⁴ is an alkoxy group (the compound of general formula (IV) is hereinafter referred to as an alkoxymethylated phenol compound); the thus obtained alkoxymethylated phenol compound (IV) is reacted with an ester having a carbon-carbon double bond of the general formula (V) -wherein R ³ is as defined above and R ⁵ is an alkyl or arylalkyl group (the compound of the general formula (V) is hereinafter referred to as an unsaturated ester) - at a temperature of not lower than 100°C to obtain a dialkyl chroman carboxylic acid ester of the general formula (VI) where R ¹ , R ² , R ³ and R ⁵ are as defined above (the compound of the general formula (VI) is hereinafter referred to as a dialkyl chroman carboxylic acid ester); the thus obtained dialkyl chroman carboxylic acid ester (VI) is hydrolyzed to obtain a dialkyl chroman carboxylic acid (I); and finally, the thus obtained dialkylchromancarboxylic acid (I) is reacted with an aromatic hydrocarbon in the presence of a Lewis acid.

The present invention also provides a dialkylchromancarboxylic acid (I) and an alkoxymethylated phenol compound (IV).

The present invention also provides a process for producing dialkylchromancarboxylic acid (I), which comprises reacting a dialkylphenol compound (III), a formaldehyde and an alcohol in the presence of a secondary amine and an acid to obtain an alkoxymethylated phenol compound (IV); reacting the thus obtained alkoxymethylated phenol compound (IV) with an unsaturated ester (V) at a temperature not lower than 100°C to obtain a dialkylchromancarboxylic acid ester (VI); and finally hydrolyzing the thus obtained dialkylchromancarboxylic acid ester (VI).

In the above-mentioned general formulas, the alkyl group represented by R', R ² , R ³ and R ⁵ is preferably a straight or branched alkyl group having 1 to 8 carbon atoms, such alkyl groups being, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, hexyl, 2-ethylhexyl or octyl, and so on. The alkoxy group represented by R ⁴ is preferably an alkoxy group having 1 to 8 carbon atoms, such alkoxy groups include, for example, methoxy, ethoxy, 1-propoxy, Ι-butoxy, Ι-hexanoxy, Ι-octanoxy, 2-ethyl-1-hexanoxy, 2-propoxy, 2-butoxy, cyclohexanoxy, 2-hydroxy-1-ethoxy, 4-hydroxy-1-butoxy, 6-hydroxy-1-hexanoxy, benzyloxy or phenethyloxy, and so on. The arylalkyl group represented by R ⁵ is preferably an arylalkyl group in which the aryl moiety has 6 to 14 carbon atoms and the alkyl moiety has 1 to 6 carbon atoms, such as benzyl or phenethyl, and so on.

In the above-mentioned Step 1, a dialkylphenol compound (III), a formaldehyde and an alcohol are reacted with each other in the presence of a secondary amine and an acid to obtain an alkoxymethylated phenol compound (IV). This alkoxymethylated phenol compound (IV) is a novel compound first provided by the present invention.

Formaldehydes include, for example, linear polymers of formaldehyde such as paraformaldehyde, etc.; cyclic acetal oligomers such as trioxane or tetraoxane, etc.; and so on. These formaldehydes may be used alone, or a combination of two or more such formaldehydes may be used.

The alcohol may be, for example, a saturated aliphatic primary alcohol such as methanol, ethanol, 1-propanol, 1-butanol, 1-hexanol, 1-octanol, 2-ethyl-1-hexanol, etc.; a saturated aliphatic secondary alcohol such as 2-propanol, 2-butanol, cyclohexanol, etc.; a saturated aliphatic diol such as ethylene glycol, 1,4-butanediol, hexylenediol, etc.; an arylalkyl alcohol such as benzyl alcohol, phenethyl alcohol; etc.; and so on. These alcohols may be used alone, or a combination of two or more of these alcohols may be used. The alkoxy group represented by R ⁴ in the above-mentioned general formula (IV) is derived from the aforementioned alcohols.

The aforementioned secondary amine and acid serve as catalysts and/or promoters in the preparation of the alkoxymethylated phenol compound.

Any aliphatic or aromatic secondary amine can be used as the secondary amine. The secondary amine may be, for example, a non-cyclic aliphatic secondary amine such as diethylamine, dibutylamine, bis(2-ethylhexyl)amine, dioctylamine, etc.; a cyclic aliphatic secondary amine such as piperidine, pyrrolidine, morpholine, etc.; an aromatic secondary amine such as N-methylaniline, N-ethylaniline, etc.; and so on. These secondary amines may be used alone, or a combination of two or more of such secondary amines may be used.

Any organic or inorganic acid can be used as the acid. In terms of selectivity, the use of organic acids is preferred. In particular, the use of saturated fatty acids having 2 to 8 carbon atoms; and aromatic fatty acids are preferred. Suitable organic acids include, for example, acetic acid, propionic acid, butyric acid, 2-methylpropanoic acid, valeric acid, 3-methylbutanoic acid, 2-methylbutanoic acid, hexanoic acid, heptanoic acid, octanoic acid, benzoic acid, and so on. These acids can be used alone or in combination of two or more of these acids.

In order to prepare the alkoxymethylated phenol compound (IV) without any problems, in the 1st Reaction Step, formaldehyde is preferably used in an amount of 0.8-10, more preferably 1-2, alcohol is preferably used in an amount of 0.8-20, more preferably 1-10, secondary amine is preferably used in an amount of 0.001-1, more preferably 0.01-0.5, and acid is preferably used in an amount of 0.01-5, more preferably 0.1-1.0, relative to 1 equivalent of dialkylphenol compound (III).

The reaction step 1 may be carried out in the presence or absence of a solvent. The solvent may be an inert solvent, such as toluene, xylene, N-methylpyrrolidone, etc. The solvent is preferably used in an amount of 50 to 1000 parts by weight relative to 100 parts by weight of the dialkylphenol compound (III).

In the first reaction step, the dialkylphenol compound (III), formaldehyde, alcohol, secondary amine, acid and, if necessary, solvent are mixed together. The reaction temperature is preferably between 50 and 150, more preferably between 80 and 120°C. In the case where the boiling point of the alcohol used is lower than the aforementioned reaction temperature, the reaction is preferably carried out under pressure. The reaction time depends on the dialkylphenol compound (III), formaldehyde, alcohol, secondary amine and acid used, but is preferably between 30 minutes and 24 hours.

Water is formed as a by-product during Reaction Step 1. If water is removed from the system during the reaction, the reaction time can be reduced.

In Reaction Step 2, the alkoxymethylated phenol compound (IV) obtained in Reaction Step 1 is reacted with an unsaturated ester (V) at a temperature not lower than 100°C to obtain a dialkyl chroman carboxylic acid ester (VI).

In the 2nd Reaction Step, the alkoxymethylated phenol compound (IV) obtained in the 1st Reaction Step can be used without isolation from the reaction mixture. However, in order to produce the dialkyl chroman carboxylic acid ester (VI) smoothly and in high yield, the obtained alkoxymethylated phenol compound (IV) must be isolated from the reaction mixture of the 1st Step and, if necessary, purified before use. For the isolation of the alkoxymethylated phenol compound (IV) from the reaction mixture of the 1st Step, for example, extraction with an aromatic hydrocarbon (e.g., toluene, xylene, etc.), ether (e.g., diisopropyl ether, etc.), or other solvent; vacuum distillation; and

and so on.

At least one unsaturated ester (V) may be used in Step 2. In order to obtain the dialkyl chroman carboxylic acid ester (VI) without any problems, the unsaturated ester (V) is preferably used in an amount of 0.8 to 20, more preferably 1.0 to 10 equivalents, relative to the alkoxymethylated phenol compound (IV).

The 2nd reaction step is preferably carried out without a solvent, but a solvent may be used. In the case where a solvent is used, an inert solvent such as decalin, mesitylene, N-methylpyrrolidone, etc. is preferably used. The solvent is preferably used in an amount of 50 to 500 parts by weight relative to 100 parts by weight of the alkoxymethylated phenol compound (IV).

The 2nd reaction step is preferably carried out in the presence of an acid. The acid acts as a catalyst and/or promoter in the preparation of the dialkyl chroman carboxylic acid ester (VI). Any organic or inorganic acid can be used as the acid, but organic acids are preferred in terms of selectivity. In particular, saturated fatty acids having 2 to 8 carbon atoms; and aromatic fatty acids are preferred. Examples of such 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, benzoic acid, and so on. These acids can be used alone or in combination of two or more of these acids. The acid is preferably used in an amount of 0.1 to 100, more preferably 1 to 10 mol%, based on the alkoxymethylated phenol compound (IV).

In the second reaction step, the alkoxymethylated phenol compound (IV), the unsaturated ester (V), and, if necessary, the acid and the solvent are mixed together at a temperature of 100°C or higher. The reaction temperature is preferably between 100 and 250°C, more preferably between 120 and 200°C. In the case where the boiling point of the unsaturated ester (V) used is lower than the aforementioned reaction temperature, the reaction is preferably carried out under pressure. The reaction time depends on the type of the alkoxymethylated phenol compound (IV) and the unsaturated ester (V) used, but is preferably between 30 minutes and 48 hours.

Alcohol is formed as a by-product during Reaction Step 2. If alcohol is removed from the system during the reaction, the reaction time can be reduced.

In Step 3, the dialkyl chroman carboxylic acid ester (VI) obtained in Step 2 is hydrolyzed to obtain a dialkyl chroman carboxylic acid (I). This dialkyl chroman carboxylic acid (I) is a novel compound first provided by the present invention.

In Step 3, the dialkyl chroman carboxylic acid ester (VI) obtained in Step 2 can be used without isolating it from the reaction mixture. However, it is preferable to isolate the dialkyl chroman carboxylic acid ester (VI) from the reaction mixture of Step 2 and, if necessary, purify it before use. For isolating the dialkyl chroman carboxylic acid ester from the reaction mixture of Step 2, for example, extraction with an aromatic hydrocarbon (e.g., toluene, xylene, etc.), ether (e.g., diisopropyl ether, etc.), or other solvent; vacuum distillation; and so on can be used.

In Reaction Step 3, the hydrolysis is preferably carried out in the presence of an acid or a base, most preferably a base.

The acid used is not particularly limited, and may include, for example, a mineral acid such as hydrochloric acid, sulfuric acid, etc.; an organic acid such as para-toluenesulfonic acid, etc.; and so on. The acid is preferably used in an amount of 0.1 to 10 mol relative to 1 mol of the dialkyl chroman carboxylic acid ester (VI).

The base used is not particularly limited, and may be, for example, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, or lithium hydroxide, etc.; an alkaline earth metal hydroxide such as calcium hydroxide, magnesium hydroxide, or barium hydroxide, etc.; and so on. The base is preferably used in an amount of 0.7 to 5 mol, more preferably 1.0 to 3 mol, relative to 1 mol of the dialkyl chroman carboxylic acid ester (VI).

In Step 3, in order to ensure that the hydrolysis reaction proceeds smoothly, an alcohol may be added to the system. The alcohol used is not particularly limited, and may include, for example, a saturated aliphatic primary alcohol such as methanol, ethanol, 1-propanol, 1-butanol, 1-hexanol, 1-octanol, 2-ethyl-1-hexanol, etc.; a saturated aliphatic secondary alcohol such as 2-propanol, 2-butanol, cyclohexanol, etc.; a saturated aliphatic diol such as ethylene glycol, 1,4-butanediol, hexylenediol, etc.; and so on. The alcohol is preferably used in an amount of 0.5 to 10, more preferably 1.0 to 3, units by weight relative to 1 unit by weight of the dialkyl chroman carboxylic acid ester (VI).

In the 3rd reaction step, the dialkyl chroman carboxylic acid ester (VI), water and, if necessary, the acid or base and the alcohol are mixed together. The reaction temperature is preferably between 20 and 120, more preferably between 50 and 100°C. In the case where the reaction temperature is higher than the boiling point of the alcohol or water used, the reaction is preferably carried out under pressure. The reaction time depends on the type of dialkyl chroman carboxylic acid ester (VI) used, but is preferably between 30 minutes and 48 hours.

In Step 4, the dialkyl chroman carboxylic acid (I) obtained in Step 3 is reacted with an aromatic hydrocarbon in the presence of a Lewis acid to give a chroman carboxylic acid (II).

In Step 4, the dialkyl chroman carboxylic acid (I) obtained in the above-mentioned Step 3 can be used without isolating it from the reaction mixture. However, it is preferable to isolate the dialkyl chroman carboxylic acid from the reaction mixture and, if necessary, purify it before use. For its isolation, for example, extraction with an aromatic hydrocarbon (e.g., toluene, xylene, etc.), ether (e.g., diisopropyl ether, etc.), or other solvent; vacuum distillation; and so on can be used.

In the case where the hydrolysis is carried out in the presence of a base, the dialkyl chroman carboxylic acid salt is preferably dissolved in an aqueous phase and extracted with an organic solvent to remove impurities such as polymer, etc.

The Lewis acid acts as a catalyst and/or promoter in Step 4 during the preparation of chroman carboxylic acid. A metal chloride is preferably used as the Lewis acid. The metal chloride used is not particularly limited, but for the sake of example, the following are mentioned: aluminum chloride, zinc chloride, iron chloride, and so on. These Lewis acids may be used alone, or a combination of two or more of these Lewis acids may be used.

The Lewis acid is preferably used in an amount of 0.1 to 5 equivalents, more preferably 0.5 to 2 equivalents, relative to one equivalent of the dialkyl chromancarboxylic acid (I), for the problem-free preparation of the chromancarboxylic acid (II).

The type of aromatic hydrocarbon used is not particularly limited, but in order to produce chromancarboxylic acid (II) without any problems, it is preferable to use, for example, an aromatic hydrocarbon having electron-donating substituents, such as toluene, xylene, cumene, etc. These aromatic hydrocarbons may be used alone, or a combination of two or more of these aromatic hydrocarbons may be used.

The aromatic hydrocarbon is preferably used in the largest possible amount for the problem-free preparation of chromancarboxylic acid (II). However, from an economic point of view, it is preferably used in an amount of 1-100 equivalents, more preferably 2-50 equivalents, relative to one equivalent of dialkylchromancarboxylic acid (I).

The 4th reaction step is preferably carried out without a solvent, but a solvent may be used. In the case where a solvent is used, an inert solvent such as hexane, heptane, etc. is preferably used. The solvent is preferably used in an amount of 50-1000 parts by weight of the dialkyl chroman14

- relative to 100 weight units of carboxylic acid (I).

In the 4th reaction step, the dialkyl chroman carboxylic acid (I), the Lewis acid, the aromatic hydrocarbon and, if necessary, the solvent are mixed together. The reaction temperature is preferably between 0 and 200°C, more preferably between 10 and 140°C. In the case where the boiling point of the aromatic hydrocarbon used is lower than the aforementioned reaction temperature, the reaction is preferably carried out under pressure. The reaction time depends on the type of dialkyl chroman carboxylic acid (I) used, but is preferably between about 30 minutes and 48 hours.

The chromancarboxylic acid (II) produced in the above-mentioned reaction can be isolated if necessary and washed or crystallized for purification. For the isolation of the chromancarboxylic acid from the reaction mixture, for example, extraction with an aromatic hydrocarbon (e.g., toluene, xylene, etc.), ether (e.g., diisopropyl ether, etc.), water or other solvent can be used; and if necessary, acid or base can be added to the reaction mixture; or vacuum distillation can be used; and so on.

The present invention is illustrated in more detail by the following examples. However, these examples are not intended to limit the scope of the present invention in any way.

Example 1

Preparation of 2,4-di-(t-butyl)-6-(butoxymethyl)-1-hydroxybenzene

472.2 g (2.29 mol) of 2,4-di-(t-butyl)-phenol, 87.3% paraformaldehyde (95.1 g, 2.77 mol), 29.6 g (0.229 mol) of di-(n-butyl)-amine, 69.8 g (1.16 mol) of acetic acid, 1183.1 g (15.96 mol) of 1-butanol and toluene were mixed together and the mixture was refluxed for 10 hours. The water formed during the reaction was removed. After the reaction was complete, the reaction mixture was washed successively with dilute aqueous sulfuric acid; with aqueous sodium bicarbonate solution; then with water and finally the organic phase was concentrated in vacuo. The residue was quantitatively analyzed by liquid chromatography according to the internal standard method. This study showed that 2,4-di-(t-butyl)-6-(butoxymethyl)-1-hydroxybenzene was prepared in 91% yield. The 'H-NMR data of the 2,4-di-(t-butyl)-6-(butoxymethyl)-1-hydroxybenzene we prepared are as follows:

ppm (CDC1 ₃ , 300 MHz) 7.27 (1H, d), 6.88 (1H, d), 4.68 (2H, s), 3.57 (2H, t, J=6.45 Hz), 1.5-1.8 (4H, m), 0.95 (3H, t, J=7.32 Hz), 1.44 (9H, s), 1.30 (9H, s).

Example 2

Preparation of 6,8-di-(t-butyl)-2-(butoxycarbonyl)chroman

To the 2,4-di-(t-butyl)-6-(butoxymethyl)-1-hydroxybenzene obtained in Example 1 (665.2 g, net 586.71 g, 2.01 mol) was added 771.2 g (6.02 mol) of butyl acrylate and 12.26 g (0.10 mol) of benzoic acid, and the mixture was stirred at 150-165°C for 30 hours. The 1-butanol formed during the reaction was removed. After the reaction was complete, the reaction mixture was quantitatively analyzed by liquid chromatography using the internal standard method. This analysis showed that 6,8-di-(t-butyl)-2-(butoxycarbonyl)chroman was prepared in 87% yield (1.74 mol). At the same time, 6,8-di-(t-butyl)-3-(butoxycarbonyl)-chroman (a positional isomer) was also formed, in an amount of about 8%. For use in the next step, the excess butyl acrylate was evaporated in vacuo, then toluene was added to the residue, and the benzoic acid was removed with aqueous sodium bicarbonate solution. The 'H-NMR data of the 6,8-di-(t-butyl)-2-(butoxycarbonyl)-chroman we prepared are as follows:

ppm (CDC1 ₃ , 300 MHz) 7.18 (1H, d), 6.90 (1H, d), 4.68 (1H, dd, J=3.48 Hz and 5.01 Hz), 4.18-4.22 (2H, m), 2.79-2.90 (2H, m), 2.28 (1H, m), 2.18 (1H, m), 1.60-1.70 (4H, m), 1.43 (9H, s), 1.30 (9H, s), 0.92 (3H, t, J=7.41 Hz).

Example 3

Preparation of 6,8-di-(t-butyl)-2-(hydroxycarbonyl)chroman

To a toluene solution of 6,8-di-(t-butyl)-2-(butoxycarbonyl)chroman obtained in Example 2 (183.0 g, 0.2 mol) were added 120.0 g of 10% aqueous sodium hydroxide solution (0.3 mol) and 120 g of methanol, and the mixture was stirred at 70°C for 2 hours. Toluene was then added to the mixture, and the mixture was stirred and then allowed to stand, and finally methanol was removed from the aqueous phase, etc. After removal, an aqueous sulfuric acid solution was added to the aqueous phase, and the mixture was extracted with toluene. The extract was concentrated in vacuo. The residue was quantitatively analyzed by liquid chromatography according to the internal standard method. This test showed that 6,8-di-(t-butyl)-2-(hydroxycarbonyl)-chroman was prepared in 98% yield (net 56.92 g, 0.196 mol). The 'H-NMR ¹⁷ • * · · · · · · ·* data of the 6,8-di-(t-butyl)-2-(hydroxycarbonyl)-chroman we prepared are as follows:

ppm (CDC1 ₃ , 300 MHz) 7.20 (1H, d), 6.93 (1H, d), 4.73 (1H, dd, J=3.45 Hz and 5.19 Hz), 2.78-2.98 (2H, m), 2.29-2.41 (1H, m), 2.12-2.28 (1H, m), 1.42 (9H, s), 1.29 (9H, m).

Example 4

Preparation of 2-chromancarboxylic acid

The 6,8-di-(t-butyl)-2-(hydroxycarbonyl)chroman obtained in Example 3 (2.90 g, 0.01 mol) was dissolved in 27 g of toluene, and the resulting solution was added dropwise to aluminum chloride (2.67 g, 0.02 mol) suspended in toluene at room temperature. The reaction mixture was then stirred at room temperature for 2 hours, then poured into an aqueous sulfuric acid solution, and finally the organic phase was separated. An aqueous alkali solution was then added to the organic phase, and then the aqueous phase was separated. An aqueous sulfuric acid solution was then added to the aqueous phase, and the mixture was extracted with toluene. The extract was concentrated in vacuo. The residue was quantitatively analyzed by liquid chromatography according to the internal standard method. This test showed that 2-chromancarboxylic acid was prepared in 90% yield (net 1.60 g, 0.009 mol). The 'H-NMR data of the 2-chromancarboxylic acid we prepared are as follows:

5 ppm (CDC1 ₃ , 300 MHz) 7.12 (2H, m), 6.92 (2H, m), 4.77 (1H, dd, J=3.57 Hz and 4.38 Hz), 2.78-2.96 (2H, m), 2.32-2.42 (1H, m), 2.17-2.27 (1H, m).

According to the present invention, chroman carboxylic acid can be produced without problems from readily available or economical starting materials ^with high yield and high productivity.

This application is based on Japanese Patent Application No. 2000-259565, the entire contents of which are incorporated herein by reference.

Claims (8)

PATENT CLAIMS 1. A process for the preparation of a chroman carboxylic acid of the general formula (II) -wherein R ³ represents a hydrogen atom or an alkyl group-, characterized in that the dialkyl chroman carboxylic acid of the general formula (I) -wherein R ¹ and R ² independently represent an alkyl group and R ³ is as defined above- is reacted with an aromatic hydrocarbon in the presence of a Lewis acid. 2. A process for the preparation of a chroman carboxylic acid of the general formula (II) -wherein R ³ represents a hydrogen atom or an alkyl group-, characterized in that in the presence of a secondary amine and an acid, a dialkylphenol compound of the general formula (III) -wherein R 1 and R 7 are as defined above-, a formaldehyde and an alcohol are reacted with each other to obtain an alkoxymethylated phenol compound of the general formula (IV) where R ¹ and R ² are as defined above and R ⁴ is an alkoxy group; the thus obtained alkoxymethylated phenol compound is reacted with an ester having a carbon-carbon double bond of the general formula (V) -wherein R is as defined above and R ⁵ is an alkyl or arylalkyl group- at a temperature not lower than 100°C to obtain a dialkyl chroman carboxylic acid ester of the general formula (VI) where R ¹ , R ² , R ³ and R ⁵ are as defined above; the thus obtained dialkyl chroman carboxylic acid ester is hydrolyzed to obtain a dialkyl chroman carboxylic acid (I) where R ¹ , R ² and R ³ are as defined above; and finally, the thus obtained dialkyl chroman carboxylic acid is reacted with an aromatic hydrocarbon in the presence of a Lewis acid. 3. The process according to claim 2, characterized in that the alkoxymethylated phenol compound of general formula (IV) and the ester having a carbon-carbon double bond of general formula (V) are reacted in the presence of an acid. 4. A dialkylchromancarboxylic acid of the general formula (I), wherein R ¹ and R ² independently represent an alkyl group and R ³ represents a hydrogen atom or an alkyl group. 5. The dialkylchromancarboxylic acid according to claim 4, wherein in the general formula (I) R ¹ and R ² are t-butyl groups, and R represents a hydrogen atom. 6. An alkoxymethylated phenol compound of the general formula (IV), wherein R ¹ and R ² are independently alkyl and R ⁴ is alkoxy. 7. The alkoxymethylated phenol compound according to claim 6, wherein in the general formula (IV), R ¹ and R ² are t-butyl groups. 8. A process for the preparation of a dialkylchromancarboxylic acid of the general formula (I) -wherein R ¹ and R ² are independently alkyl and R is hydrogen or alkyl, characterized in that a dialkylphenol compound of the general formula (III) -wherein R and R are as defined above-, a formaldehyde and an alcohol are reacted with each other in the presence of a secondary amine and an acid to obtain an alkoxymethylated phenol compound of the general formula (IV) -wherein R and R are as defined above and R ⁴ is an alkoxy group; the alkoxymethylated phenol compound thus obtained is reacted with an ester having a carbon-carbon double bond of general formula (V) -wherein R is as defined above and R ⁵ is an alkyl or arylalkyl group- at a temperature not lower than 100°C to obtain a dialkylchromancarboxylic acid ester of general formula (VI) where R ¹ , R ² , R ³ and R ⁵ are as defined above; and finally the dialkylchromancarboxylic acid ester thus obtained is hydrolyzed. * Dl -'Tu' The authorized person is a member of the SBG _council in the VAT area Budapest, Andrássy út 113. Telephone: 461-1000 Fax: 461-1099