JP2621306B2 - Method for producing optically active benzene derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a compound represented by the general formula (I): (In the formula, R represents an alkyl group or an alkoxyalkyl group having 1 to 20 carbon atoms. N is 1 or 2, and an asterisk indicates an asymmetric carbon.) A method for producing the same.

<Prior Art> The optically active benzene derivative represented by the general formula (I) is useful as an organic electronic material, and is also used as an intermediate for pharmaceuticals, agricultural chemicals, and the like. Nothing is known about optically active benzene derivatives, and of course, no production method is known.

<Problems to be Solved by the Invention> The optically active benzene derivative represented by the general formula (I) is useful as an organic electronic material as described above.
In particular, it is important as an intermediate of a liquid crystal compound, and can be led to a liquid crystal compound by reacting with a phenol, for example, as shown below, and the compound has extremely excellent properties as a ferroelectric liquid crystal. ing.

<Means for Solving the Problems> The present invention relates to the novel and useful compound represented by the general formula (I)
Wherein the optically active benzene derivative is represented by the general formula (II): (Wherein A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom, and R, n and * have the same meanings as described above). It can be manufactured by the following.

This debenzylation reaction is usually carried out by catalytically hydrogenating or hydrolyzing the optically active ether derivative (II) with hydrogen in the presence of a hydrogenation catalyst.

In the debenzylation reaction by catalytic hydrogenation, a palladium-based metal catalyst is preferably used as a hydrogenation catalyst, and specific examples thereof include palladium-carbon, palladium oxide, palladium black, and palladium chloride.

The amount of the catalyst to be used is usually 0.001 to 0.5 times by weight, preferably 0.001 times by weight, based on the optically active ether derivative (II).
The range is 5 to 0.3 times by weight. The reaction is usually carried out in a solvent such as water, dioxane, tetrahydrofuran, methanol, ethanol, n-propyl alcohol, acetone, dimethylformamide, toluene,
Solvents which are inert to the reaction, such as aliphatic hydrocarbons such as dichloromethane and ethyl acetate, aromatic hydrocarbons, alcohols, ethers, ketones, esters, and halogenated hydrocarbons, alone or in a mixture, are used.

This reaction is carried out at a hydrogen pressure of normal pressure or under pressure, and the amount of hydrogen absorbed is an optically active ether derivative (I
It is preferable to set the reaction end point when it becomes 1 to 1.2 equivalent times of I).

The reaction temperature ranges from -10C to 100C, preferably from 10C to 60C.

After completion of the reaction, the desired optically active benzene derivative (I) can be obtained by removing the catalyst from the reaction mixture by filtration or the like, and then concentrating it. It can be purified by chromatography or the like.

The debenzylation by the hydrolysis method is carried out by hydrolyzing an optically active ether derivative (II) in the presence of an acid or an alkali. Because it is not stable,
Hydrolysis in the presence of alkali is generally advantageous.

Examples of the alkali used for the hydrolysis include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, calcium hydroxide, and the like, and alkali metal (hydrogen) carbonates. And alkaline earth metal carbonates. These are preferably used as an aqueous solution. The amount of the alkali to be used is usually 1 equivalent or more of the optically active ether derivative (II), and is usually 1 to 10 times.
It is used in a range of equivalent times.

This reaction requires at least one equivalent of water relative to the optically active ether derivative (II), and the reaction is usually carried out in the presence of an excess amount of water. Water-soluble organic solvents such as ethanol and tetrahydrofuran are preferred.).

The reaction temperature is usually in the range of −20 ° C. to 100 ° C., and the reaction time is not particularly limited.

After the completion of the reaction, the organic solvent is removed from the reaction mixture, if necessary, and the reaction solution is subjected to acid precipitation with an acid, followed by extraction, concentration, and the like to obtain the desired optically active benzene derivative (I). be able to.

The optically active ether derivative (II) as a raw material in this reaction is represented by the general formula (III) (Wherein, A, n and * have the same meanings as described above). An optically active alcohol represented by the general formula (IV) RX (wherein R has the same meaning as described above, X indicates ". where R" halogen atom or -OSO ₂ R may be prepared by reacting with an alkylating agent represented by.) of a lower alkyl group or an optionally substituted phenyl group .

This alkylation reaction is usually carried out in the presence of a basic substance. Examples of the basic substance include alkali metal hydrides such as sodium hydride and potassium hydride, and water such as sodium hydroxide, potassium hydroxide and calcium hydroxide. Examples thereof include alkali metal oxides or alkaline earth metal hydroxides, alkali metal carbonates such as sodium carbonate and potassium carbonate, butyllithium and the like, and alkali metals such as lithium, sodium and potassium.

Such basic substances are optically active alcohols (III)
Is required to be 1 equivalent or more, and the upper limit is not particularly limited, but is preferably in the range of 1 to 5 equivalents.

The alkylating agent (IV) used in this reaction refers to a halide or a sulfate such as chloride, bromide, iodine or the like having an alkyl group or an alkoxyalkyl group having 1 to 20 carbon atoms as exemplified below. Methanesulfonic acid ester, ethanesulfonic acid ester, benzenesulfonic acid ester, toluenesulfonic acid ester, etc.).

Methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, isopropyl, isobutyl, 2-butyl
Methylbutyl, 2-methylhexyl, isopentyl, 2
-Methyloctyl, methoxymethyl, methoxyethyl,
Methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, methoxyheptyl, methoxyoctyl, methoxynonyl, methoxydecyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, ethoxyheptyl, ethoxyoctyl, ethoxynonyl , Ethoxydecyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, propoxyhexyl, propoxyoctyl, propoxydecyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, butoxyhexyl, butoxyheptyl, butoxy Nonyl, pentyloxymethyl, pentyloxyethyl, pentyloxypropyl, Chill oxy butyl, pentyl oxy pentyl, pentyloxy octyl, pentyloxy decyl, hexyl oxymethyl, hexyl oxyethyl, hexyl oxypropyl, hexyloxy butyl,
Hexyloxypentyl, hexyloxyhexyl, hexyloxyoctyl, hexyloxynonyl, hexyloxydecyl, heptyloxymethyl, heptyloxyethyl, heptyloxypropyl, heptyloxypentyl, octyloxymethyl, octyloxyethyl, decyloxymethyl, decyloxy Ethyl, decyloxypropyl.

Incidentally, these groups may be optically active groups having an asymmetric carbon.

The amount of the alkylating agent (IV) to be used is not less than 1 equivalent times the amount of the optically active alcohol (III), but is usually in the range of 1 to 5 equivalents.

Examples of the reaction solvent include aliphatic or aromatic hydrocarbons such as tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone, toluene, benzene, chloroform, chlorobenzene, dichloromethane, dichloroethane, carbon tetrachloride, dimethylformamide, and hexane; A single or mixture of solvents inert to the reaction of hydrocarbons or the like, or a polar solvent such as dimethyl sulfoxide, hexamethylphosphorylamide, N-methylpyrrolidone or the like is used, and the amount thereof is not particularly limited.

The reaction temperature is usually −50 ° C. to 120 ° C., preferably −30 ° C.
It is in the range of ~ 100 ° C.

After completion of the reaction, usual separation means such as extraction, liquid separation,
An optically active ether (II) can be obtained in good yield by an operation such as concentration, which can be purified by column chromatography, recrystallization, etc., if necessary. It can be used as it is.

The optically active alcohols (III), which are the raw materials in this reaction, have the general formula (V) (Wherein A and n have the same meanings as described above, and R ′ represents a lower alkyl group.) Wherein one of the optically active forms of the esters is hydrolyzed. It can be produced by hydrolyzing one of the optically active forms of the esters (asymmetric hydrolysis) using an esterase having an ability.

The microorganism that produces an esterase used in this reaction may be any microorganism that produces an esterase having the ability to asymmetrically hydrolyze the esters (V), and is not particularly limited.

In addition, the esterase in the present invention means esterase in a broad sense including lipase.

Specific examples of such microorganisms include, for example, Enterobacter, Arthrobacter, Brevibacterium, Pseudomonas, Alcaligenes, Micrococcus, Chromobacterium, Microbacterium, Corynebacterium, Bacillus, Lactobacillus, Trichoderma, Candida, Saccharomyces, Rhodotorula, Cryptococcus, Torulopsis, Pichia, Penicillium, Aspergillus,
Microorganisms belonging to the genera Rhizopus, Mucor, Aureopacidium, Actinomucor, Nocardia, Streptomyces, Hansenula, and Achromobacter are exemplified.

The culture of the microorganism is performed according to a conventional method. For example, a culture solution can be obtained by using a liquid solvent.

For example, sterilized liquid medium [for molds and yeasts, malt extract / yeast extract medium (5 g of peptone, 10 g of glucose, 3 g of malt extract, 3 g of yeast extract in water 1;
Inoculated with microorganisms in a sweetened bouillon medium (dissolve 10 g of glucose, 5 g of peptone, 5 g of meat extract, and 3 g of NaCl in water 1 to pH 7.2) for bacteria, usually 20 to 40
Performed by reciprocal shaking culture for 1 to 3 days at
If necessary, solid culture may be performed.

Some of these microbial esterases are commercially available and can be easily obtained. Specific examples of commercially available esterases include, for example, the following.

Pseudomonas lipase [lipase P (manufactured by Amano Pharmaceutical)], Aspergillus lipase [lipase AP (manufactured by Amano Pharmaceutical)], Mucor lipase [lipase M-AP]
(Manufactured by Amano Pharmaceutical Co., Ltd.)], lipase of Candida cylindrasse [lipase MY (manufactured by each sugar industry)], lipase of the genus Alcaligenes [lipase PL (manufactured by Meito Sangyo)], lipase of the genus Achromobacter [lipase AL Sugar industry)),
Lipases of the genus Arthrobacter [lipase joint BSL (joint liquor purification)], lipases of the genus Chromobacterium (manufactured by Toyo Brewery), lipases of Rhizopus delemar [talipase (manufactured by Tanabe Seiyaku)], lipases of the genus Rhizobus [lipase syrup] Ken (Osaka Bacteria Research Institute)].

Also, animal and plant esterases can be used,
Specific examples of these esterases include the following.

Steabsin, pancreatin, pig liver esterase, Wheat Germ esterase.

As the esterase used in this reaction, an enzyme obtained from an animal, a plant, or a microorganism is used. The enzyme may be used in the form of a purified enzyme, a crude enzyme, an enzyme-containing substance, a microorganism culture solution, a culture, a cell, a culture medium, It can be used as needed in various forms such as a liquid and a product obtained by treating them, and a combination of an enzyme and a microorganism can also be used. Alternatively, it can be used as an immobilized enzyme immobilized on a resin or the like, or an immobilized cell.

The asymmetric hydrolysis reaction is generally carried out by vigorously stirring a mixture of the starting ester (V) and the above enzyme or microorganism in a buffer.

As the buffer, sodium phosphate which is usually used,
A buffer solution of an inorganic acid salt such as potassium phosphate, a buffer solution of an organic acid salt such as sodium acetate or sodium citrate, or the like is used, and its pH is 8 to 11 in a culture solution of an alkaliphilic bacterium or an alkaline esterase. PH 5 to 8 is preferable for a culture solution of a non-alkaline microorganism or an esterase having no alkali resistance. The concentration is usually in the range of 0.05-2M, preferably 0.05-0.5M.

The reaction temperature is usually from 10 to 60 ° C, and the reaction time is generally from 3 to 70 hours, but is not limited thereto.

After completion of the hydrolysis reaction, the hydrolysis reaction solution is extracted with a solvent such as methyl isobutyl ketone, ethyl acetate, ethyl ether, or the like, and the solvent is distilled off from the organic layer, and the concentrated residue is subjected to column chromatography. Optically active alcohols (III) which are hydrolysis products and optically active esters which remain as hydrolysis products [optically active compounds in raw material esters (V) which have not been hydrolyzed] Can be separated.

The optically active esters obtained here may be further hydrolyzed, if necessary, to be enantiomers of the optically active alcohols previously obtained.

When a lipase belonging to the genus Pseudomonas or Arthrobacter is used as the lipase in this asymmetric hydrolysis reaction, an optically active alcohol (III) with relatively high optical purity can be obtained.

During the hydrolysis, toluene,
It is also possible to use an effective solvent inert to the reaction such as chloroform, methyl isobutyl ketone, and dichloromethane.
By using these, asymmetric hydrolysis can be advantageously performed.

Esters (V), which are the starting materials for this reaction, have the general formula (VI) (Wherein A and n have the same meanings as described above). The alcohol can be produced by reacting a lower alkyl carboxylate with an alcohol to acylate the alcohol.

In the acylation, an acid anhydride or an acid halide of a lower alkyl carboxylic acid is used as the lower alkyl carboxylic acid, and specifically, acetic anhydride, acetic chloride or bromide, propionic anhydride, propionic chloride or bromide, butyryl Chloride or bromide,
Examples include valeyl chloride or bromide.

In this reaction, the amount of the lower alkyl carboxylic acid to be used must be at least 1 equivalent times the alcohol (VI), and the upper limit is not particularly limited, but is preferably 4
Equivalent times.

This reaction is carried out by using a catalyst usually in the presence or absence of a solvent.

When a solvent is used in this reaction, examples of the solvent include tetrahydrofuran, ethyl ether,
Acetone, methyl ethyl ketone, toluene, benzene,
An aliphatic or aromatic hydrocarbon such as chloroform, chlorobenzene, dichloromethane, dichloroethane, carbon tetrachloride, dimethylformamide, or hexane, an ether, or a solvent inert to a reaction such as a halogenated hydrocarbon is used alone or in combination. The amount used is not particularly limited.

Examples of the catalyst include dimethylaminopyridine, diethylaminopyridine, triethylamine, tri-n-
Organic or inorganic basic substances such as butylamine, pyridine, picoline, imidazole, sodium carbonate, potassium hydrogencarbonate, and the like, and organic or inorganic acids such as toluenesulfonic acid, methanesulfonic acid, and sulfuric acid may be used as a catalyst. it can.

The amount of catalyst used depends on the type of lower alkyl carboxylic acids used, the combination of catalysts used, etc.
Although not necessarily specified, for example, when an acid halide is used as a lower alkyl carboxylic acid, it is 1 equivalent or more times the acid halide.

The reaction temperature is usually -30C to 100C, preferably -20C to 90C.

The reaction time is not particularly limited, and the alcohols (V
The point at which I) disappears from the reaction system can be regarded as the reaction end point.

After completion of the reaction, usual separation means such as extraction, liquid separation,
The ester (V) can be obtained in good yield by concentration, recrystallization, etc., which can be further purified by column chromatography or the like, if necessary, but can be used as is in the reaction mixture in the next step.

Furthermore, the alcohols (VI), which are the raw materials for this reaction,
General formula (VII) (Wherein, A and n have the same meanings as described above) can be produced by reducing with a reducing agent capable of reducing ketone to alcohol.

As such a reducing agent, sodium borohydride, lithium borohydride or borohydride is preferably used. The amount of the reducing agent is at least 1 equivalent times or more based on the starting ketones (VII), and usually 1 to The range is 10 equivalent times.

This reaction is usually performed in a solvent. Examples of such a solvent include tetrahydrofuran, dioxane, ethyl ether, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, ethers such as toluene, benzene, chloroform, dichloromethane, halogenated hydrocarbons, and the like. Or a mixture of solvents inert to the reaction, such as alcohols and the like.

The reaction temperature is usually in the range of -30C to 100C, preferably in the range of -20C to 90C.

From the reaction mixture thus obtained, alcohols (VI) are obtained by operations such as liquid separation, concentration, distillation and crystallization.
Can be obtained in good yield, but it is not always necessary to isolate the alcohols (VI) in order to obtain the esters (V) in the next step, and the reaction mixture may proceed to the next step.

The ketones (VII), which are the starting materials for such a reaction, can be easily produced by reacting bezyl halides and acetylcarboxylic acids by a conventional method, for example, as shown below.

<Effect of the Invention> Thus, according to the method of the present invention, an optically active benzene derivative represented by the general formula (I), which is a novel compound, can be produced with high optical purity and high yield. It is useful not only as an intermediate for agricultural chemicals and pharmaceuticals, but also very useful as an intermediate for liquid crystal compounds.

<Example> Hereinafter, the present invention will be described with reference to examples.

Example 1 30.49 g (0.12 mol) of 4-acetylbenzoic acid benzyl ester was placed in a four-necked flask equipped with a stirrer and a thermometer.
50 ml of ethanol and 150 ml of chloroform are charged, and 2.3 g (0.06 mol) of sodium borohydride is added thereto at 15 to 25 ° C over 10 minutes.

After keeping at the same temperature for 2 hours, the reaction mixture is poured into ice water and extracted twice with 200 ml of ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure to give 2- (1-hydroxyethyl) benzoic acid benzyl ester (VI-1) (29.2 g)
(95% yield).

▲ n ²⁵ _D ▼ 1.5680 Next, 27.95 g (0.11 mol) of (VI-1) obtained above was dissolved in a mixed solution consisting of 150 ml of toluene and 50 ml of pyridine, and 9.42 g (0.12 mol) of acetyl chloride was added thereto. ~ 20 ℃
Add in 2 hours. 1 hour at the same temperature, 30-35 ℃
Incubate for 2 hours. After completion of the reaction, the reaction mixture was cooled to 10 ° C. or lower, and thereto was added 3N hydrochloric acid (300 ml), and the organic layer was separated.
Wash sequentially with 5% aqueous sodium bicarbonate and water. The organic layer is concentrated under reduced pressure, further purified by column chromatography, and benzyl 4- (1-acetoxyethyl) benzoate (V-1)
32.14 g (98% yield) were obtained.

19.08 g (64 mmol) of (V-1) obtained above were mixed with 400 ml of 0.1 M phosphate buffer (pH 7.0), 10 ml of chloroform and 4 g of amanolipase "P", and the mixture was vigorously stirred at 40 to 45 ° C. for 20 hours. I do.

After completion of the reaction, the reaction mixture was treated with methyl isobutyl ketone 60
Extract with 0ml. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a mixture of hexane: ethyl acetate = 12: 1 as an eluent to give (+)-4- (1-hydroxyester) phenylcarboxylic acid benzyl ester ( III-1) 7.21 g [▲ (α) ²⁵ _D ▼ + 35.4 ゜ (c = 1, C
HCl ₃ ), ▲ n ²⁵ _D ▼ 1.5691].

1.28 g (5 mmol) of (III-1) obtained here is dissolved in 15 ml of dimethylformamide and cooled to 10 ° C. 0.15 g (6 mmol) of sodium hydride was added thereto, and 30-35
Incubate at ℃ for 1 hour. Next, 2.1 g of n-dodecyl sylate
(6 mmol) at 20-25 ° C. and react at 40 ° C. for 5 hours. After completion of the reaction, the reaction mixture is poured into ice and extracted with 50 ml of ethyl acetate. After washing the organic layer with water,
Concentrate under reduced pressure. The concentrated residue is purified by column chromatography, and 1.74 g (82% yield) of benzyl (II-1) benzoate (+)-4- (1-dodecyloxyethyl) benzoate is obtained.
Obtained.

▲ n ²⁵ _D ▼ = 1.5016 ▲ [α] ²⁵ _D ▼ + 32.4 ゜ (c = 1, CHCl ₃ ) Next, 1 g of (II-1) (2.5 mmol, 5% Pd-carbon (50
% Wet), 10 ml of methanol and 5 ml of ethyl acetate are mixed and hydrogenated under normal pressure. When the hydrogen absorption reaches 60 ml, the reaction is stopped, the catalyst is removed separately, and the liquid is concentrated. The residue was chromatographed using toluene-acetic acid (20: 1) to give (+)-4- (1-dodecyloxyethyl).
0.72 g of benzoic acid (I-1) was obtained.

Melting point 49.5-50 ° C ▲ [α] ²⁵ _D ▼ + 32.7 ゜ (c = 1, CHCl ₃ ) Example 2 0.5 g (1.2 mmol) of (II-1) obtained in Example 1, 10
A 1.5% aqueous solution of sodium hydroxide and 10 ml of methanol are mixed and reacted at 25 to 30 ° C. for 5 hours. After the reaction,
The pH is adjusted to 3 with 10% hydrochloric acid and extracted with 20 ml of toluene. The organic layer was washed with water, concentrated under reduced pressure, and the residue was purified by chromatography to obtain 0.37 g of (+)-4- (1-dodecyloxyethyl) benzoic acid (I-1).

Melting point 49.5-50.5 ° C ▲ [α] ²⁵ _D ▼ + 32.6 ゜ (c = 1, CHCl ₃ ) Example 3 2.56 g (0.01 mol) of [III-1] obtained in Example 1 was converted to N-
Dissolve in 20 ml of methylpyrrolidone and cool to 10 ° C. To this, add 0.31 g (0.013 mol) of sodium hydride and add 30 to 35
Incubate at ℃ for 1 hour. Next, 3.6 g of n-hexyltosylate
(0.014 mol) at 20 to 25 ° C. and react at 40 ° C. for 5 hours. After completion of the reaction, the reaction mixture is poured on ice and extracted with 50 ml of ethyl acetate. The organic layer is washed with water and concentrated under reduced pressure. The concentrated residue was purified by column chromatography, and (+)-4- (1-hexyloxyethyl)
3.11 g of benzyl benzoate (II-2) (yield 92
%).

1.69 g (5 mmol) of (II-2) obtained above, 5% Pd-
0.1 g of carbon and 15 ml of ethanol are mixed and hydrogenated under normal pressure. The reaction was stopped when the amount of hydrogen absorbed reached 120 ml, and post-treated and purified according to Example 1 to obtain (+)-
4- (1-hexyloxyethyl) benzoic acid (I-2)
1.21 g (97.5% yield) was obtained.

▲ n ²⁵ _D ▼ 1.5040 ▲ [α] ²⁵ _D ▼ + 65.4 ゜ (c = 1, CHCl ₃ ) Example 4 0.85 g (2.5 mmol) of (II-2) obtained in Example 3, 5 ml of tetrahydrafuran And 5% aqueous potassium hydroxide solution 5
g and react at 20 ° C. for 5 hours. After the reaction, 1
Adjust the P ^H 2 at 0% aqueous hydrochloric acid and evaporated to remove the tetrahydrofuran under reduced pressure. The residue was extracted with 20 ml of toluene, and the organic layer was washed with water and purified according to Example 2 (+)
-4 (1-hexyloxyethyl) benzoic acid (I-2)
0.6 g (96% yield) was obtained.

▲ n ²⁵ _D ▼ 1.5038 ▲ [α] ²⁵ _D ▼ + 64.4 ゜ (c = 1, CHCl ₃ ) Example 5 The same flask as used in Example 1 was charged with 32.17 g of methyl benzyl 4-acetylbenzoate (0.12 Mol), 50 ml of ethanol, 100 ml of dichloromethane and 50 ml of tetrahydrofuran, to which 2.3 g (0.06 mol) of sodium borohydride are added over 10 minutes at 15 to 25 ° C. After keeping the mixture at the same temperature for 2 hours, the reaction mixture was poured into ice water, and post-treated in the same manner as in Example 1 to give 4- (1-hydroxyethyl) benzoic acid methylbenzyl ester (VI-
3) 31.48 g (97% yield) was obtained.

Next, 29.71 g (0.11 mol) of (VI-3) obtained here was dissolved in a mixture of 200 ml of dichloromethane and 50 ml of pyridine, and 50 ml of a dichloromethane solution containing 9.42 g (0.12 mol) of acetyl chloride was added thereto at room temperature. Drip. After about 2 hours, the reaction solution is poured into 300 ml of 3N hydrochloric acid, and an extraction operation is performed. The organic layer is washed successively with water, 7% aqueous sodium bicarbonate and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 33.3 g (97% yield) of 4- (1-acetoxyethyl) benzoic acid methylbenzyl ester (V-3) as a pale yellow oil.

15.6 g (50 mmol) of (V-3) obtained above was mixed with 200 ml of 0.3 M phosphate buffer (pH 7.0), 10 ml of chloroform and 3 g of amanolipase "P", and stirred vigorously at 38 to 40 ° C for 24 hours. I do.

After completion of the reaction, the reaction mixture is extracted with 600 ml of ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was subjected to column chromatography separation and purification using a fitting solution of hexane: ethyl acetate = 12: 1 as an eluent to give (+)-4- (1-hydroxyethyl) benzoic acid. Methyl benzyl ester (III-3)
5.95 g [▲ [α] ²⁵ _D ▼ ＋ 36.3 ゜ (c = 1, CHCl ₃ ) 、 ▲
n ²⁵ _D ▼ 1.5688].

1.35 g (5 mmol) of (III-3) obtained above are dissolved in 15 ml of dimethylformamide and cooled to 10 ° C. 0.15 g (6 mmol) of sodium hydride is added to this, and 30-35 ° C
Incubate for 1 hour. Next, 1.55 g (6 mmol) of ω-ethoxypropyl tosylate was added at 20 to 25 ° C.
React for 5 hours at ° C. After completion of the reaction, post-treatment and purification were carried out in the same manner as in Example 1 to give (+)-4- (1-ω-ethoxypropoxyethyl) benzoic acid methylbenzyl ester (II
-3) 1.37 g (77% yield) was obtained.

Next, 0.89 g (2.5 mmol) of (II-3), 5% Pd-C0.1
g and methanol (10 ml) are mixed and catalytically hydrogenated under normal pressure. The reaction is terminated when the hydrogen absorption reaches 60 ml,
Thereafter, post-treatment and purification were carried out according to Example 1, and (+)-4-
(1-ω-ethoxypropoxyethyl) benzoic acid (I-
3) 0.61 g (97% yield) was obtained.

▲ n ²⁵ _D ▼ 1.5077 ▲ [α] ²⁵ _D ▼ + 59.7 ゜ (c = 1, CHCl ₃ ) Example 6 4-Acetylbenzoic acid methoxybenzyl ester 34.0 instead of 4-acetylbenzoic acid methylbenzyl ester
Except for using 9 g (0.12 mol), the same reaction and work-up were conducted in the same molar scale as in Example 5 to obtain the following intermediate.

4- (1-hydroxyethyl) benzoic acid methoxybenzyl ester (VI-4) yield 95.5% 4- (1-acetoxyethyl) benzoic acid methoxybenzyl ester (V-4) yield 98.5% (+)-4- (1-hydroxyethyl) benzoic acid methoxybenzyl ester (III-4) 2.34 g ▲ [α] ²⁵ _D ▼ + 37.2 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5721 4) Dissolve 1.43 g (5 mmol) in 15 ml of dimethylformamide and cool at 10 ° C. 0.15 g (6 mmol) of sodium hydride was added thereto, and 30-35
Incubate at ℃ for 1 hour. Then, 2.1 g (15 mmol) of methyl iodide was added at 20 to 25 ° C., and at the same temperature for 3 hours,
Incubate at 40 ° C for 3 hours. After completion of the reaction, post-treatment and purification were conducted in the same manner as in Example 1 to give (+)-4- (1-methoxyethyl) benzoic acid methoxybenzyl ester (II-4) 1.36.
g (91% yield) was obtained.

Next, 0.75 g (2.5 mmol) of (II-4) obtained above, 0.03 g of palladium oxide and 10 ml of methanol are mixed and subjected to catalytic hydrogenation under normal pressure. The reaction was terminated when the hydrogen absorption amount reached 63 ml, and post-treated and purified according to Example 1 to obtain (+)-4- (1-methoxyethyl) benzoic acid (I-
4) 0.43 g (95% yield) was obtained.

Melting point 99-100 ° C ▲ [α] ²⁵ _D ▼ + 94.2 ゜ (C = 1, CHCl ₃ ) Example 7 A flask similar to that used in Example 1 was charged with 4′-acetyl-4-biphenylcarboxylic acid benzyl ester 33.0. g
(0.1 mol) and 200 ml of tetrahydrofuran and 50 ml of ethanol, and 3.8 g (0.1 mol) of sodium borohydride are added at 15 to 25 ° C over 10 minutes. After keeping at the same temperature for 2 hours, the reaction solution is poured into ice water and extracted twice with 300 ml of chloroform. The organic layer was washed with water and concentrated under reduced pressure to obtain 32.9 g (yield: 99%) of benzyl 4 '-(1-hydroxyethyl) -4-biphenylcarboxylate (VI-5).

29.9 g (0.09 mol) of (VI-5) obtained here was dissolved in toluene 1
Dissolve in 50 ml and 50 ml of pyridine, to which 9.42 g (0.12 mol) of acetyl chloride are added over 2 hours at 15-20 ° C. Thereafter, it is kept at the same temperature for 2 hours and at 40 to 45 ° C. for 2 hours. After the reaction is completed, cool to 10 ° C or less, then add 3N hydrochloric acid
After adding 300 ml, the organic layer is separated and then washed successively with water, 5% sodium hydrogen carbonate and water. The organic layer was concentrated under reduced pressure, and the residue was further purified by column chromatography to give 4'-
33.0 g (98% yield) of (1-acetoxyethyl) -4-biphenylcarboxylic acid benzyl ester (V-5) was obtained.

29.9 g (0.08 mol) of (V-5) obtained here was mixed with 800 ml of 0.1 M phosphate buffer (pH 7.5), 30 ml of chloroform and 6 g of amanolipase "P", and vigorously stirred at 30 to 35 ° C for 20 hours. I do. After completion of the reaction, the reaction mixture is extracted with 600 ml of methyl isobutyl ketone.

The organic layer is concentrated under reduced pressure, and the residue is purified by column chromatography using a chloroform: ethyl acetate (12: 1) mixture as an eluting solvent to give (+)-4 '-(1-hydroxyethyl) -4.
-Biphenylcarboxylic acid benzyl ester (III-5) 1
0.6 g [▲ [α] ²⁵ _D ▼ +23.7 ゜ (c = 1.0, CHCl ₃ ), melting point 104-106 ° C.] was obtained.

1.66 g (5 mmol) of the obtained [III-5] is dissolved in 20 ml of dimethylformamide and cooled to 10 ° C. 0.15 g (6 mmol) of sodium hydride was added thereto, and 30-35
Incubate at ℃ for 1 hour. Next, 1.7 g of n-octyl tosylate
(6 mmol) at 20-25 ° C. and react at 40 ° C. for 5 hours. After completion of the reaction, the reaction mixture is poured on ice and extracted with 50 ml of chloroform. The organic layer is washed with water and concentrated under reduced pressure. The concentrated residue was purified by column chromatography to obtain 1.49 g (81%) of (+)-4 '-(1-octyloxyethyl) -4-biphenylcarboxylic acid benzyl ester (II-5). (▲ (α) ²⁰ _D
▼ + 26.2 ゜ (c = 1, CHCl ₃ )] 1.03 g (2.8 mmol) of (II-5) obtained above, 5% Pd-
0.1 g of carbon, 15 ml of tetrahydrofuran and 5 m of methanol
and mix and contact hydrogenate under normal pressure. 66 ml of hydrogen absorption
The reaction is terminated when it becomes. After removing the catalyst separately, the solution was concentrated and then purified by chromatography to obtain (+)-4 '.
0.76 g (98% yield) of-(octyloxyethyl) -4-biphenylcarboxylic acid (I-5) was obtained.

▲ [α] ²⁵ _D ▼ + 67.5 ゜ (c = 1, CHCl ₃ ) Melting point 139-140 ° C. Example 8 1.66 g (5 mmol) of [III-5] obtained in Example 7 is dissolved in 20 ml of dimethylformamide. And cool to 10 ° C. 0.15 g (6 mmol) of sodium hydride was added thereto, and 30
Incubate at ~ 35 ° C for 2 hours. Then 1.22 g of propyl bromide
(10 mmol) is added at 20 to 25 ° C, and the mixture is reacted at the same temperature for 2 hours and further at 40 to 50 ° C for 5 hours. After completion of the reaction, post-treatment and purification were carried out according to Example 7, and (+)-4'-
1.50 g (yield 80%) of (1-propoxyethyl) -4-biphenylcarboxylic acid benzyl ester (II-6) was obtained.

1.05 g (2.8 mmol) of (II-6) obtained above, 5% Pd-
0.1 g of carbon, 15 ml of tetrahydrofuran and 5 m of methanol
and hydrogenate under normal pressure. Hydrogen absorption amount 68ml
Stop the reaction when it becomes. After removing the catalyst separately, the solution was concentrated and the residue was purified by chromatography (eluent: chloroform / acetic acid = 10/1) to give (+)-4 '-(1-
Propoxyethyl) -4-biphenylcarboxylic acid (I-
6) 0.77 g (97.5% yield) was obtained.

▲ [α] ²⁵ _D ▼ + 76.9 ゜ (c = 1, CHCl ₃ ) Melting point 172 ° -173 ° C. Example 9 The same flask as used in Example 1 was charged with p-chloro 4′-acetyl-4-biphenylcarboxylate. 36.5 g (0.1 mol) of benzyl ester, 150 ml of chloroform and 50 ml of ethanol are charged, and 3.8 g (0.1 mol) of sodium borohydride is added at 15 to 25 ° C over 10 minutes. After keeping at the same temperature for 2 hours, the reaction solution was poured into ice water, and ethyl acetate 20
Extract twice with 0 ml. The organic layer was washed with water and concentrated under reduced pressure to give 4 '-(1-hydroxyethyl) -4-biphenylcarboxylic acid p-chlorobenzyl ester (VI-7) 36.5
g (99.5% yield).

33.0 g (0.09 mol) of (VI-7) obtained here was mixed with toluene 1
Dissolve in 50 ml and 50 ml of pyridine, to which 9.42 g (0.12 mol) of acetyl chloride are added over 2 hours at 15-20 ° C. Thereafter, it is kept at the same temperature for 1 hour and at 40-50 ° C for 2 hours. After completion of the reaction, the reaction mixture is cooled to 10 ° C. or lower, and thereto is added 3N hydrochloric acid (300 ml). The organic layer is separated, and washed successively with water, 5% sodium hydrogen carbonate and water. The organic layer was concentrated under reduced pressure, and the residue was further purified by column chromatography to give 4'-
36.4 g of (1-acetoxyethyl) -4-biphenylcarboxylic acid p-chlorobenzyl ester (V-7) (yield 99.
0%).

32.7 g (0.08 mol) of (V-7) obtained here was mixed with 800 ml of 0.1 M phosphate buffer (pH 7.5), 30 ml of chloroform and 6 g of amanolipase "P", and the mixture was vigorously stirred at 40 to 45 ° C for 20 hours. I do. After completion of the reaction, the reaction mixture is extracted with 600 ml of methyl isobutyl ketone.

The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a hexane: ethyl acetate (12: 1) mixture as an eluent to give (+)-4 '-(1-hydroxyethyl) -4-biphenylcarboxylic acid p-chlorobenzyl ester (III
-7) 13.8 g [▲ [α] ²⁰ _D ▼ + 21.7 ゜ (c = 0.544, CHC
l _3), melting point from 108 to 110.5 ° C.] and unreacted ester 16.5g
I got

3.65 g (10 mmol) of the obtained [III-7] is dissolved in 30 ml of dimethylformamide and cooled to 10 ° C. 0.48 g (12 mmol) of sodium hydride was added thereto, and 30-35
Incubate at ℃ for 1 hour. Next, n-octadecyl tosylate
5.1 g (12 mmol) is added at 20 to 25 ° C. and reacted at 40 ° C. for 5 hours. After completion of the reaction, pour the reaction mixture into ice,
Extract with 50 ml of ethyl acetate. The organic layer is washed with water and concentrated under reduced pressure. The concentrated residue was purified by column chromatography, and 5.07 g (82% yield) of (+)-4 '-(1-octadecyloxyethyl) -4-biphenylcarboxylic acid p-chlorobenzyl ester (II-7) was obtained. Obtained. [▲ [α] ²⁰ _D ▼ + 21.1 ゜ (c = 0.98, CHCl ₃ ), ▲
n ²⁰ _D ▼ 1.5314] Next, 3.1 g of the obtained (II-7), 0.5 g of 5% Pd-carbon,
40 ml of tetrahydrofuran and 10 ml of methanol are mixed and hydrogenated under normal pressure. The reaction is terminated when the amount of hydrogen absorbed reaches 120 ml. The catalyst was removed separately, and the solution was concentrated and purified by chromatography using chloroform / acetic acid (10/1) to purify (+)-4 '-(1-octadecyloxyethyl) -4-biphenylcarboxylic acid (I-7). I got

〔[Α] ²⁵ _D ▼ + 55.8 ゜ (c = 1, CHCl ₃ ) Melting point 145-146 ° C. Example 10 1.28 g (5 mmol) of [III-1] obtained in Example 1 are dissolved in 15 ml of dimethylformamide. And cool to 10 ° C. Next, 0.15 g (6 mmol) of sodium hydride was added, and 30 to 3
Incubate at 5 ° C for 1 hour. To this was added 1.45 g (6 mmol) of S-2-methylbutyl tosylate at 20 to 25 ° C.
The reaction is carried out at 5050 ° C. for 5 hours. Thereafter, post-treatment and purification were carried out according to Example 1, and (+)-4- (1-S-2'-methylbutoxyethyl) benzoic acid benzyl ester (II-8)
1.40 g (86% yield) were obtained.

Then, using (II-8) 0.81 g (2.5 mmol), 0.2 g of 5% Pd-carbon (50% wet) and 15 ml of methanol, the reaction, post-treatment and purification were carried out in the same manner as in Example 1 to obtain (+) -4- (1
-S-2'-methylbutoxyethyl) benzoic acid (I-
8) 0.58 g (98% yield) was obtained.

▲ n ²⁵ _D ▼ 1.4718 ▲ [α] ²⁵ _D ▼ + 46.8 ゜ (c = 1, CHCl ₃ )

Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number in the agency FI Technical display location // C12P 41/00 C12P 41/00 F

Claims (5)

(57) [Claims] 1. A compound of the general formula (II) (Wherein, R represents an alkyl group or an alkoxyalkyl group having 1 to 20 carbon atoms, A represents a hydrogen atom, a lower alkyl group,
Shows a lower alkoxyl group or a halogen atom. n is 1
Or 2, and * represents an asymmetric carbon. Wherein the optically active ether derivative represented by the formula (I) is debenzylated: (Wherein, R, n and * have the same meanings as described above). 2. A compound of the general formula (III) (Wherein, A, n and * have the same meanings as described above) and an optically active alcohol represented by the general formula (IV) R-X (IV) (wherein R has the same meaning as described above) And X represents a halogen atom or —OSO ₂ R ″, wherein R ″ represents a lower alkyl group or a phenyl group optionally substituted with a lower alkyl group.) A method for producing an optically active benzene derivative represented by the general formula (I), which comprises obtaining an optically active ether derivative represented by the general formula (II), followed by debenzylation. 3. Formula (V) (Wherein, A and n have the same meanings as described above, and R ′ represents a lower alkyl group.) Wherein one of the optically active forms of the esters is preferentially used. Asymmetric hydrolysis using an esterase having the ability to hydrolyze to obtain an optically active alcohol represented by the general formula (III), and then converting the optically active alcohol to an alkylating agent represented by the general formula (IV) To obtain an optically active ether derivative represented by the general formula (II), followed by debenzylation of the derivative to produce an optically active benzene derivative represented by the general formula (I). 4. A compound of the general formula (VI) (Wherein A and n have the same meanings as described above) by reacting an alcohol represented by the following formula with a lower alkyl carboxylic acid to obtain an ester represented by the general formula (V),
Then, an asymmetric hydrolysis using an esterase having an ability to preferentially hydrolyze one of the optically active forms of the esters to obtain an optically active alcohol represented by the general formula (III), Then, the optically active alcohol is reacted with an alkylating agent represented by the general formula (IV) to obtain an optically active ether derivative represented by the general formula (II),
Then, a process for producing an optically active benzene derivative represented by the general formula (I), which is debenzylated. 5. A compound of the formula (VII) (Wherein, A and n have the same meanings as described above) to obtain an alcohol represented by the general formula (VI), and then the alcohol and a lower alkyl carboxylic acid are combined with each other. The ester is reacted to obtain an ester represented by the general formula (V), and then is subjected to asymmetric hydrolysis using an esterase having an ability to preferentially hydrolyze one of the optically active forms of the ester. General formula (III)
To obtain an optically active alcohol derivative represented by the general formula (II) by reacting the optically active alcohol with an alkylating agent represented by the general formula (IV). And a method for producing an optically active benzene derivative represented by the general formula (I), which is followed by debenzylation.