JP2580698B2 - Optically active benzene derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a compound represented by the general formula (I): (Wherein, R represents an alkyl group or an alkoxyalkyl group which may contain a halogen atom having 1 to 20 carbon atoms,
n represents 1 or 2, and * represents an asymmetric carbon).

<Prior Art> The optically active benzene derivative represented by the general formula (I) is a novel compound which has not been described in any literature, and its production method as well as its usefulness as a compound have been completely known. Not been.

<Problems to be Solved by the Invention> The optically active benzene derivative represented by the above general formula (I) is also useful as an intermediate for pharmaceuticals, agricultural chemicals, etc. Very useful.

<Means for Solving the Problems> The present invention is not limited to such a medical or agricultural chemical intermediate,
An object of the present invention is to provide an optically active benzene derivative represented by the above general formula (I), which is a novel compound useful as an intermediate of an organic electronic material, especially a liquid crystal compound.

The present inventors have developed such a new and useful general formula (I)
As a result of an investigation on a method for producing an optically active benzene derivative represented by the formula (1), the present invention was reached.

The present invention provides the following: [First step] General formula (II) (Wherein A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom; n is 1 or 2), and a ketone represented by the general formula (III) (Wherein A and n have the same meanings as described above) [Second step] The alcohol represented by the general formula (III) obtained in the first step is converted to a lower alkyl carboxylic acid With the general formula (IV) (Wherein A and n have the same meanings as described above; R ′ represents a lower alkyl group.) [Third step] [Third step] The step of obtaining the general formula (IV) obtained in the second step ) Is subjected to asymmetric hydrolysis using an esterase capable of hydrolyzing one of the optically active isomers of the ester to give a compound of the general formula (V) (Wherein, A and n have the same meaning as described above, and the asterisk indicates an asymmetric carbon). Step of obtaining an optically active alcohol represented by the following formula: The optically active alcohol represented by the general formula (V) is converted into a compound represented by the general formula (VI) R-COOH (VI) (wherein R is an alkyl group which may contain a halogen atom having 1 to 20 carbon atoms or An aliphatic carboxylic acid represented by the following formula (VII): (Wherein, A, R, n and * have the same meanings as described above) [Fifth step] The step of obtaining an optically active ester represented by the general formula (VII) obtained in the fourth step The optically active esters are debenzylated to give a compound of the formula (I)
In the step of obtaining an optically active benzene derivative represented by the following, the first to fifth steps, the second to fifth steps, the third to
This is a method for producing an optically active benzene derivative represented by the general formula (I), comprising a fifth step, fourth to fifth steps, and a fifth step.

 Hereinafter, the present invention will be described in detail.

The ketones (II) as the raw materials in the first step are, for example, as shown below, benzyl halides and p-
It can be easily obtained by reacting hydroxyphenyl ketone.

The reduction of ketones (II) is performed using a reducing agent capable of reducing ketone to alcohol.

As such a reducing agent, sodium borohydride, lithium aluminum hydride or borohydride is preferably used, and its use amount is at least 1 equivalent or more based on the raw material ketones, and is usually in the range of 1 to 10 equivalents. It is.

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 generally in the range of -80C to 100C, preferably in the range of -20C to 90C.

From the reaction mixture thus obtained, an alcohol (II) is obtained by operations such as liquid separation, concentration, distillation, and crystallization.
Although I) can be obtained in good yield, alcohols (III) are not necessarily required to obtain esters (IV) in the next step.
Need not be isolated, and the reaction mixture may proceed to the next step.

The reaction for obtaining the esters (IV) from the alcohols (III) (second step) is carried out by reacting the alcohols (III) with lower alkyl carboxylic acids to effect acylation.

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 is at least 1 equivalent to the alcohol (III), and the upper limit is not particularly limited, but is preferably 4 or less.
Is equivalent.

This reaction is performed by using a catalyst 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, triethylamine, tri-n-butylamine, picoline,
Examples thereof include organic or inorganic basic substances such as imidazole, sodium carbonate, and potassium hydrogen carbonate, and organic or inorganic acids such as toluenesulfonic acid, methanesulfonic acid, and sulfuric acid can also be used as a catalyst.

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 alkylcarboxylic acid, the amount is at least 1 equivalent to the acid halide.

The reaction temperature is usually -80 ° C to 90 ° C, preferably-
20 ° C to 90 ° C.

The reaction time is not particularly limited, and alcohols (II
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,
Ester (IV) 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.

Esters (IV) to optically active alcohols (V)
(Eighth step) is to hydrolyze one of the optically active esters by using an esterase having the ability to hydrolyze one of the optically active esters (asymmetric hydrolysis) ).

The microorganism that produces an esterase used in this reaction may be any microorganism that produces an esterase having the ability to asymmetrically hydrolyze esters (IV), 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, Previbacterium, 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 cultivation of the microorganism is usually performed according to a conventional method. For example, a culture solution can be obtained by performing liquid culture.

For example, a sterilized liquid medium [malt extract / yeast extract medium for molds and yeasts (peptone 5 g, glucose 10 g, malt extract 3 g, yeast extract 3 g dissolved in water 1, p
H6.5), for bacteria, inoculated with microorganisms in a heated bouillon medium (10 g of glucose, 5 g of peptone, 5 g of meat extract and 3 g of Nacl dissolved in water 1 to pH 7.2)], usually 20 to 40
The culture is performed by reciprocating shaking culture at 1 ° C. for 1 to 3 days, and solid culture may be performed if necessary.

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 (Amano Pharmaceutical) Aspergillus lipase [Lipase AP (Amano Pharmaceutical)], Mucor lipase AP (Amano Pharmaceutical), Candida
Sylindrasse lipase [Lipase MY (Meito Sangyo)], Alkaliner lipase [Lipase PL (Meito Sangyo)], Achromobacter lipase [Lipase AL (Meito Sangyo)], Arthrobacter Lipase [Shin Nippon Kagaku], Chromobacterium lipase (Toyo Brewery), Rhizopus delemar lipase [Taripase (Tanabe Seiyaku)], Rhizopus lipase [Lipase Saiken (Osaka Bacteria Research Institute)] .

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

Stearpsin, 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 usually carried out by vigorously stirring a mixture of the raw material esters (IV) and the above-mentioned enzyme or microorganism in a buffer solution.

As the buffer, sodium phosphate which is usually used,
A buffer of an inorganic acid salt such as potassium phosphate, a buffer 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, and the pH is 8 to 11. Cultures of non-microorganisms and esterases that do not have alkali resistance
pH 5-8 is preferred. The concentration is usually 0.05-2M, preferably
It is in the range of 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 (V), which are hydrolysis products, and optically active esters, which are the residue of the hydrolysis, among the optically active compounds in the raw material esters (IV), which were not hydrolyzed Can be decomposed.

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

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

In addition, at the time of this asymmetric hydrolysis, an organic solvent which is inert to the reaction such as toluene, chloroform, methyl isobutyl ketone, and dichloromethane can be used in addition to the buffer solution. It can be performed advantageously.

The reaction (fourth step) for obtaining the optically active ethers (VII) from the optically active alcohols (V) is performed by converting the optically active alcohols (V) into a compound represented by the general formula (VI) R-COOH (VI) , R represents an alkyl group or an alkoxyalkyl group which may contain a halogen atom having 1 to 20 carbon atoms.), Or an aliphatic carboxylic acid or a derivative thereof.

Examples of R in the general formula (VI) include the following alkyl groups or alkoxyalkyl groups.

Methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, 1-methylethyl, 2-methylbutyl, 2 , 3-dimethylbutyl, 2,3,3-trimethylbutyl, 2-methylpentyl, 3-methylpentyl, 2,3-
Dimethylpentyl, 2,4-dimethylpentyl, 2,3,3,4-
Tetramethylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 2,5-dimethylhexyl, 2-methylheptyl, 2-methyloctyl, 2-methylhexyl
Trihalomethylpentyl, 2-trihalomethylhexyl, 2-trihalomethylheptyl, 2-halopropyl,
3-halo-2-methylpropyl, 2,3-dihalopropyl, 2-halobutyl, 3-halobutyl, 2,3-dihalobutyl, 2,4-dihalobutyl, 3,4-dihalobutyl, 2-halo-3-methylbutyl, -Halo-3,3-dimethylbutyl, 2-halopentyl, 3-halopentyl, 4-halopentyl, 2,4-dihalopentyl, 2,5-dihalopentyl,
2-halo-3-methylpentyl, 2-halo-4-methylpentyl, 2-halo-3-monohalomethyl-4-methylpentyl, 2-halohexyl, 3-halohexyl, 4-
Halohexyl, 5-halohexyl, 2-haloheptyl,
2-halooctyl (in the above alkyl group, halo represents fluorine, chlorine, bromine or iodine), 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, propoxy Hexyl, propoxyoctyl, propoxydecyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, butoxy Kishihekishiru, Butokishihepuchiru, Butokishinoniru, pentyloxymethyl, pentyloxy ethyl, pentyl oxy propyl, pentyl oxy butyl, pentyl oxy pentyl, pentyloxy octyl, pentyloxy decyl, hexyl oxymethyl, hexyl oxyethyl, hexyl oxypropyl,
Hexyloxybutyl, hexylhexpentyl, hexyloxyhexyl, hexyloxyoctyl, hexyloxynonyl, hexyloxydecyl, heptyloxymethyl, heptyloxyethyl, heptyloxypropyl, heptyloxypentyl, octyloxymethyl, octyloxyethyl, decyl Oxymethyl, decyloxyethyl, decyloxypropyl.

In the above reaction, an aliphatic halide such as an aliphatic carboxylic acid or an anhydride or an acid chloride or an acid bromide thereof is used.

In addition, these aliphatic carboxylic acids or derivatives thereof may be any of racemic forms and optically active forms.

Some of the above optically active carboxylic acids are obtained by oxidation of the corresponding alcohol, reductive deamination of the amino acid. Others can be derived from optically active amino acids and optically active oxyacids that are naturally occurring or obtained by resolution, such as:

Alanine, valine, leucine, isoleucine, phenylalanine, serine, threonine, alosreonine, homoserine, alloisoleucine, tert-leucine, 2-aminobutyric acid, norvaline, norleucine, ornithine, lysine, hydroxylysine, phenylglycine, trifluoroalanine, asparagine Acid, glutamic acid, lactic acid,
Mandelic acid, trobic acid, 3-hydroxybutyric acid, malic acid, tartaric acid, isopropylmalic acid and the like.

The reaction of such an optically active alcohol compound (V) with an aliphatic carboxylic acid or a derivative thereof is generally performed in the presence or absence of a solvent, generally in the presence of a catalyst.

When a solvent is used in this reaction, examples of the solvent include aliphatic or aromatic solvents such as tetrahydrofuran, ethyl ether, acetone, methyl ethyl ketone, toluene, benzene, chlorobenzene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethylformamide, and hexane. Solvents which are inert to the reaction of the group hydrocarbons, ethers, halogenated hydrocarbons and the like, alone or in a mixture. The amount can be used without any particular limitation.

In the case of using an acid anhydride or an acid halide of the above-mentioned aliphatic carboxylic acid in the reaction, the use amount thereof is required to be at least 1 equivalent times to the optically active alcohol compound (V). Although not particularly limited, it is preferably 4 equivalent times.

Examples of the catalyst include dimethylaminopyridine, triethylamine, tri-n-butylamine, pyridine,
Picoline, collidine, imidazole, sodium carbonate,
Organic or inorganic basic substances such as sodium methylate and potassium bicarbonate can be mentioned. Further, an organic acid or an inorganic acid such as toluenesulfonic acid, methanesulfonic acid, or sulfuric acid can be used as a catalyst.

In using such a catalyst, for example, when an acid halide of an aliphatic carboxylic acid is used as a raw material, pyridine and triethylamine are particularly preferably used.

The amount of the catalyst used depends on the type of the acid anhydride or acid halide of the aliphatic carboxylic acid and the combination of the catalyst to be used, etc., and is not necessarily specified.For example, when the acid halide is used, It is 1 equivalent times or more.

When an aliphatic carboxylic acid is used in the reaction, the carboxylic acid is usually dehydrated and condensed by using 1 to 2 equivalents of the optically active alcohol (V) in the presence of a condensing agent. Optically active ethers (VII) can be obtained.

As the condensing agent, carbodiimides such as N, N'-dicyclohexylcarbodiimide and N-cyclohexyl-N '-(4-diethylamino) cyclohexylcarbodiimide are preferably used. If necessary, organic bases such as 4-pyrrolidinopyridine, pyridine and triethylamine are used. Are used together.

The amount of the condensing agent to be used is 1 to 1.2 equivalent times relative to the carboxylic acid, and when a base is used, the amount to be used is 0.01 to 0.2 equivalent times to the condensing agent.

The reaction temperature is usually -80C to 100C, preferably -25C to 80C.

The reaction time is not particularly limited, and the time when the optically active alcohol compound as the raw material disappears can be regarded as the end point of the reaction.

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

The reaction for obtaining the desired optically active benzene derivative from the optically active ethers (VII) (fifth step) is usually carried out by
The reaction is carried out by subjecting an optically active ether to dehydrogenation by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst.

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

The amount of the catalyst used is determined by the amount of the optically active ether (VI
I) Usually 0.001 to 0.5 times by weight, preferably 0.005 to
The range is 0.3 times by weight. The reaction is usually performed in a solvent,
Examples of the solvent include water, dioxane, tetrahydrofuran, methanol, ethanol, n-propyl alcohol, acetone, dimethylformamide, toluene, dichloromethane, aliphatic hydrocarbons such as ethyl acetate, aromatic hydrocarbons, alcohols, ethers, ketones, esters, and the like. A single or mixture of solvents inert to the reaction such as halogenated hydrocarbons is 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 (VII)
It is preferable to set the reaction end point when the amount becomes 1 to 1.2 equivalent times with respect to.

The reaction temperature ranges from -10C to 100C, preferably from 10C to 90C.

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

<Effect of the Invention> Thus, according to the method of the present invention, a novel compound, an optically active benzene derivative represented by the general formula (I), can be industrially advantageously produced, and the compound of the present invention is useful for liquid crystals. Not only is it useful as a material, it can also be used as an intermediate for agricultural chemicals, pharmaceuticals, and the like.

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

Example 1 In a four-necked flask equipped with a stirrer and a thermometer, 90.45 g (0.4 mol) of 4-benzyloxyacetophenone (II-1), 800 ml of tetrahydrofuran and 100 ml of methanol were placed.
To which 15.14 g (0.4 mol) of sodium borohydride are added over 2 hours at 15-25 ° C. After keeping at the same temperature for 5 hours, the mixture is poured into ice water and extracted twice with 500 ml of ethyl acetate. The organic layer was concentrated under reduced pressure, and 88.5 g of p-benzyloxy 1-phenethyl alcohol (III-1) was obtained.
(97% yield).

Next, 68.44 g (0.8 mol) of the obtained (III-1) was dissolved in a mixture of 800 ml of toluene and 50 ml of pyridine, and 25.91 g (0.33 mol) of acetyl chloride was added thereto at 15 to 20 ° C.
Add it over time. Then, at the same temperature for 1 hour, 40-50
Incubate at ° C for 2 hours. After the reaction is completed, cool to 10 ° C or less,
Add 200 ml of water. The separated organic layer was washed with 2N aqueous hydrochloric acid, water,
After sequentially washing with 5% sodium carbonate and water, the mixture was concentrated under reduced pressure, and further purified by column chromatography to obtain p-benzyloxy-1-phenethyl alcohol acetate (IV-
1) 79.8 g (98.5% yield) was obtained.

Next, 67.5 g (0.25 mol) of (IV-1) obtained above is vigorously stirred at 40 to 45 ° C. for 40 hours together with 700 ml of 0.3 M phosphate buffer (pH 7.5) and 6.75 g of amano lipase “P”. After completion of the reaction, the reaction mixture was extracted with 500 ml of ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography using a toluene: ethyl acetate (5: 2) mixed solution as an eluent, and (+) -P-benzyloxy-1-phenethyl alcohol [V-1] 23.38 g (41% yield)
[Α] ²⁰ _D ▼ + 35.9 ゜ (c = 1, CHCl ₃ ), melting point 66-68
° C].

Next, the (+)-p-benzyloxy-1-
1.14 g (5 mmol) of phenethyl alcohol (V-1)
Is dissolved in 15 ml of dry pyridine, and 0.51 g (5.5 mmol) of propionic chloride is added dropwise thereto. After stirring for 1 hour at room temperature, the mixture was poured into 100 ml of 2N hydrochloric acid,
Extract with 50 ml of toluene. The toluene layer is washed with water, washed with a 7% aqueous sodium bicarbonate solution, further washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off from this toluene solution under reduced pressure, and the obtained residue was purified by column chromatography packed with silica gel to give (+)-
5.35 g (99% yield) of propionate ester (VII-1) of p-pendyloxy-1-phenethyl alcohol was obtained.

This was further purified by recrystallization using ethanol.

[▲ [α] ²⁵ _D ▼ = + 93 ° (c = 1, CHCl ₃ ) Melting point: 52 ° C. Next, 1.14 g (4 mmol) of (VII-1) obtained here was treated with 10 ml of methanol and 0.2% of 5% Pd-carbon 0.2%. g and then contact hydrogenated under a hydrogen atmosphere at normal pressure. 100ml hydrogen absorption
When the reaction becomes, stop the reaction and remove the catalyst separately.
The solution was concentrated, and the residue was purified by column chromatography using a mixture of toluene and ethyl acetate (5: 2) as an eluent to give (+)-4- (1′-propionyloxyethyl).
0.73 g (93.5%) of phenol was obtained. [▲ [α] ²⁰ _D ▼ +
92 ° (c = 1, CHCl ₃ ), melting point 71-72 ° C.] Example 2 1.14 g (5 mmol) of (+)-p-benzyloxy-1-phenethyl alcohol (V-1) obtained in Example 1 ,
20 ml of toluene, 5 ml of pyridine and 1.18 g of hexanoic anhydride
(5.5 mmol) at 30-40 ° C for 5 hours. After completion of the reaction, the reaction solution is poured into ice water, and extracted by adding 20 ml of toluene. Thereafter, washing is performed sequentially with 1N-hydrochloric acid solution, 2% sodium bicarbonate water and water. After that, after-treatment and purification according to Example 1,
1.58 g of hexanoic acid ester (VII-2) of (+)-p-benzyloxy-1-phenethyl alcohol (97% yield)
I got

▲ [α] ²⁵ _D ▼ +73 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5289 Next, 1.30 g (4 mmol) of (VII-2) obtained here were treated with 10 ml of methanol and 0.2% of 5% Pd-carbon 0.2%. g, and then contact hydrogenated under a hydrogen atmosphere at normal pressure. The reaction is stopped when the hydrogen absorption amount is 95 ml, and the catalyst is removed separately. The solution was concentrated, and the residue was purified by column chromatography to give (+)-4-
0.85 g of (1'-hexanoyloxyethyl) phenol
(90% yield).

▲ [α] ²⁵ _D ▼ = + 79 ゜ (c = 1, CHCl ₃ ), ▲ n ²⁵ _D ▼
1.5101 Example 3 4'- flask in a four-necked flask equipped with a stirrer and thermometer
Acetyl-4-benzyloxybiphenyl (II-3) 1
2.09 g (0.04 mol), 40 ml of tetrahydrofuran and 10 ml of methanol are charged, and 1.51 g (0.4 mol) of sodium borohydride is added thereto over 2 hours at 15 to 25 ° C. After keeping at the same temperature for 5 hours, the mixture is poured into ice water and extracted twice with 50 ml of chloroform. The organic layer is concentrated under reduced pressure to give 4-benzyloxy-4 '-(1-hydroxyethyl)
11.74 g (yield 96.5%) of biphenyl (III-8) was obtained.

Next, 9.12 g (0.3 mol) of 4-benzyloxy-4 '-(1-hydroxyethyl) biphenyl was dissolved in a mixture of 40 ml of toluene and 10 ml of pyridine, and 2.59 g (0.033 mol) of acetyl chloride was added to 15 ml of the mixture. Add at 2020 ° C. over 2 hours. Incubate at the same temperature for 1 hour and at 40-50 ° C for 2 hours.

After completion of the reaction, the mixture is cooled to 10 ° C. or lower, 30 ml of water is added, and the organic layer is separated, and washed successively with 1N hydrochloric acid, water, 5% sodium carbonate and water. The organic layer was concentrated under reduced pressure, and further purified by column chromatography to give 4-benzyloxy-
10.16 g (yield 97.8%) of 4 '-(1-hydroxyethyl) biphenyl acetate (IV-3) was obtained.

8.65 g (0.025 mol) of this acetic ester (IV-3) was added to 0.1 g
Mix with 200 ml of 3M phosphate buffer (pH 7.5) and 5 g of Amano lipase "P" and stir vigorously at 40-45 ° C for 120 hours. After completion of the reaction, the reaction mixture is extracted with 100 ml of chloroform. The organic layer was concentrated under reduced pressure, and the residue was dissolved in toluene:
Purification by column chromatography using a 5: 2 mixture of ethyl acetate as an eluting solvent gave (+)-4-benzyloxy-4 '-(1-
2.89 g of hydroxyethyl) biphenyl (V-3) [▲
[Α] ²⁰ _D ▼ + 34.8 ゜ (c = 1, CHCl ₃ ), mp 158-15
9 ° C].

Next, 1.22 g (4 mmol) of (V-3) obtained above is dissolved in 10 ml of dichloromethane and 10 ml of pyridine, and 0.71 g (4.4 mmol) of octanoic acid chloride is added at 20 ° C. After stirring at the same temperature for 3 hours and at 40-50 ° C for 2 hours, the mixture is poured into ice water and extracted with dichloromethane. The organic layer is sequentially washed with 1N-hydrochloric acid solution, 2% sodium bicarbonate water and water. The organic layer is purified by silica gel column chromatography after concentration. Octanoic acid ester of (+)-4-benzyloxy-4 '-(1-hydroxyethyl) biphenyl (VII
-3) was obtained. 1.64 g (yield 95.5%) ▲ [α] ²⁵ _D ▼ + 43 ゜ (c = 1, CHCl ₃ ) Melting point 92-93 ° C. Next, 1.29 g (3 mmol) of (VII-3) obtained here was treated with tetrahydrofuran. 20ml, methanol 5ml and 5% pd
Mixed with 0.25 g of carbon and contact hydrogenated under a hydrogen atmosphere at normal pressure. The reaction is stopped at a hydrogen absorption of 70 ml, and the catalyst is separated. Hereinafter, purification is performed in the same manner as in Example 1.

(+)-4- (1'-octanoyloxyethyl-
0.9 g (88% yield) of 4'-hydroxybiphenyl was obtained.

▲ [α] ²⁵ _D ▼ +39 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5536 Example 4 (+)-4-benzyloxy-4′- obtained in Example 3
1.22 g of (1-hydroxyethyl) biphenyl (V-3)
(4 mmol), 0.72 g (4.8 mmol) of (2s, 3s) -2-chloro-8-methylpentanoic acid and dichloromethane
0.91 g of dicyclohexylcarbodiimide in 20 ml of solution
(4.4 mmol) and 0.03 g of 4-pyrrolidinopyridine are added and reacted at room temperature for 10 hours. After the completion of the reaction, the separated dicyclohexylurea is removed separately, and the solution is concentrated under reduced pressure. The concentrated residue is purified by silica gel column chromatography (elution solvent: toluene). (+)-4
-(2S, 3S) -2-chloro-3-methylpentanoic acid ester of benzyloxy-4 '-(1-hydroxyethyl) biphenyl is obtained (VII-4). 1.68 g (yield 95.5%) ▲ [α] ²⁵ _D ▼ +68.3 ゜ (c = 1, CHCl ₃ ) Melting point 125-126 ° C. Next, 1.31 g (3 mmol) of (VII-4) obtained here With 10 ml of tetrahydrofuran, 3 ml of toluene and 2% pd-
It is mixed with 0.1 g of carbon and subjected to catalytic hydrogenation under a hydrogen atmosphere. After completion of the reaction, the mixture was separately purified by post-treatment in the same manner as in Example 1 to give (+)-4-hydroxy-4 '-(1- (2'S,
3'S-2-chloro-3-methylpentanoyloxy)
0.32 g (31% yield) of ethyl) biphenyl are obtained.

▲ [α] ²⁵ _D ▼ = + 60 ° (c = 1, CHCl ₃ ) Melting point 99 ° -100 ° C. Example 5 In the same apparatus as in Example 1, 4- (p-methylbenzyloxy) acetophenone (II-5) 24.0 g (0.1 mol), 100 ml of chloroform and 30 ml of methanol are charged, and 4.5 g (0.12 mol) of sodium borohydride is added thereto at 15 to 20 ° C. over 2 hours. After keeping it at the same temperature for 5 hours, it is poured into ice water and extracted with chloroform. The organic layer was concentrated under reduced pressure to give p- (4-methylbenzyloxy) -1-
23.1 g (95.5% yield) of phenethyl alcohol (III-5)
I got

Next, 18.16 g (0.075 mol) of (III-5) obtained here,
6.48 g (82.5 mmol) of acetyl chloride was added to a mixed solution of 100 ml of toluene and 15 ml of pyridine at 10 to 20 ° C.
Add in time. After keeping the temperature at the same temperature for 1 hour, keep it at 40-50 ° C for another 2 hours. The post-treatment and purification were carried out according to Example 1 to give p- (4-methylbenzyloxy) -1-
20.78 g of acetic acid ester of phenethyl alcohol (IV-5)
(97.5% yield).

Next, 19.2 g (70 mmol) of (IV-5) was added to 200 ml of 0.3 M phosphate buffer (pH 7.0) and amano lipase “P” 2.
Stir vigorously for 20 hours at 35-40 ° C with 88g. After completion of the reaction, post-treatment and purification are performed according to Example 1.

6.6 g of (+)-p- (4-methylbenzyloxy) -1-phenethyl alcohol (V-5) (89% yield)
[Α] ²⁰ _D ▼ + 34.2 ° (c = 1, CHCl ₃ ), melting point 52-58 ° C.].

Next, 1.21 g (5 mmol) of (V-5) obtained here was mixed with 1.65 g (6 mmol) of palmitic acid chloride and pyridine 1
The reaction is carried out at 25-30 ° C. for 10 hours with 0 ml and 10 ml of toluene. Hereinafter, post-treatment and purification are performed according to Example 1.

Palmitic acid ester of (+)-p- (4-methylbenzyloxy) -1-phenethyl alcohol (VII-
5) 2.16 g (90% yield) are obtained.

▲ [α] ²⁵ _D ▼ + 58 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5186 Then, using 1.86 g (4 mmol) of (VII-5), debenzylation was carried out in the same manner as in Example 1. The reaction, work-up and purification give 1.41 g (94%) of (+)-4- (1'-palmitoyloxyethyl) phenol as a waxy solid.

▲ [α] ²⁰ _D ▼ + 58 ゜ (c = 1, CHCl ₃ ) Example 6 4- (p-methoxybenzyloxy) acetophenone (II-6) 25, instead of 4- (p-methylbenzyloxy) acetophenone A reduction reaction was carried out in the same manner as in Example 1 except that 6 g (0.1 mol) of p- (4-methoxybenzyloxy) -1-phenethyl alcohol (III-6) was used.
Get. Next, 0.075 mol of (III-6) was subjected to an acetylation reaction, post-treatment and purification in the same manner as in Example 5 to give the acetate ester of p- (4-methoxybenzyloxy) -1-phenethyl alcohol. (IV-6) is obtained (96% yield).

Asymmetric hydrolysis reaction, post-treatment and purification are carried out in the same manner as in Example 5 except that this (IV-6) is used. (+)-P- (4
-Methoxybenzyloxy) -1-phenethyl alcohol (V-6) is obtained (yield 35%).

This (V-6) was subjected to an acylation reaction, post-treatment and purification in the same manner as in Example 5 except that decanoic acid chloride was used instead of palmitic acid chloride, whereby (+)-p
-(4-Methoxybenzyloxy) -1-phenethyl alcohol decanoate (VII-6) is obtained (yield 9
6%).

Next, (VII-6) was subjected to a debenzylation reaction, post-treatment and purification in the same manner as in Example 1 to obtain (+)-4- (1′-decanoyloxyethyl) phenol in a yield of 90%. Was.

▲ [α] ²⁵ _D ▼ = + 52 ° (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.4912 Example 7 4′-Acetyl-4- (p-) in place of 4′-acetyl-4-benzyloxybiphenyl The reduction reaction and work-up are carried out in the same manner as in Example 3 except that 18,46 g (0.04 mol) of chlorobenzyloxy) -biphenyl is used. Further, the subsequent reactions are carried out under the same molar ratios and conditions as in Example 3, and further post-treated and purified. (+)-4-
(P-Chlorobenzyloxy-4 '-(1-hydroxyethyl) biphenyl (V-7) is obtained.

An acylation reaction and a post-treatment were carried out in the same manner as in Example 3 except that propionic acid chloride was used instead of octanoic acid chloride to give (+)-4- (p-chlorobenzyloxy-
4 '-(1-hydroxyethyl) biphenyl propionate (VII-7) is obtained.

{[Α] ²⁵ _D ▼ = + 44} (c = 1, CHCl ₃ ) Next, 3 mmol of (VII-7) is subjected to a debenzylation reaction, post-treatment and purification according to Example 3.

(+)-4- (1'-propionyloxyethyl)-
4'-Hydroxybiphenyl is obtained.

▲ [α] ²⁵ _D ▼ = + 60 ° (c = 1, CHCl ₃ ) Melting point 136-138 ° C. Examples 8-10 Except for using the acid chloride (5.5 mmol) shown in Table 1 in place of propionic acid chloride. The acylation reaction and work-up were carried out as in Example 1. The next debenzylation reaction is
Starting from 4 mmol of the compound of the formula (VII), 15 ml of tetrahydrofuran, 3 ml of toluene and 2% pd-carbon
Hydrogenate after adding 0.1 g. After completion of the reaction, post-treatment and purification were performed according to Example 1. Table 1 shows the results.

Example 11 Propionic acid chloride in place of octanoic acid chloride
The reaction and work-up were carried out under the same conditions as in Example 3 except that 0.41 g (4.4 mmol) was used, and (+)-4-benzyloxy-4 '-(1-propionyloxyethyl) biphenyl (VII-11) ) 1.40 g (97.5% yield).

▲ [α] ²⁵ _D ▼ + 55 ゜ (c = 1, CHCl ₃ ) melting point 125 ° C. Then, using 1.08 g (3 mmol) of (VII-11),
Contact hydrogenation is carried out in the same manner as in Example 3. Thereafter, post-treatment and purification were carried out in the same manner to obtain 0.75 g (yield 98%) of (+)-4-hydroxy-4 '-(1-propionyloxyethyl) biphenyl.

▲ [α] ²⁵ _D ▼ + 52 ° (c = 1, CHCl ₃ ) Melting point 133 ° -135 ° C. Example 12 (+)-4-benzyloxy-4 ′-(1-hydroxyethyl) biphenyl (V-3) Instead of (+)-p-
Benzyloxy-1-phenethyl alcohol (V-1)
1.14 g (4 mmol) was added to (2S, 3S) -2-chloro-3-
2-S-methylbutanoic acid 0.49 instead of methylpentanoic acid
The acylation reaction, work-up and purification are carried out in the same manner as in Example 4 except that g (4.8 mmol) is used.

2- (S) -methylbutanoic acid ester of (+)-p-benzyloxy-1-phenethyl alcohol (VII-12) 1.3
6 g (95% yield) was obtained.

▲ [α] ²⁵ _D ▼ +88 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁰ _D ▼ 1.5826 Then, (VII-12) 0.94 g (3 mmol), ethyl acetate
15 ml and 0.3 g of 5% pd-carbon are mixed and catalytically hydrogenated at normal pressure. Post-treatment and purification were carried out according to Example 1.

0.61 g (yield 91.5%) of (+)-4- [1'-2S-2-methylbutyryloxyethyl) phenol was obtained.

▲ [α] ²⁰ _D ▼ +38.2 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁰ _D ▼ 1.4976 Example 13 Acetate ester of (−)-p-benzyloxy-1-phenethyl alcohol obtained in Example 1 13.5 g, methanol 1
A mixture of 00 ml and 30 g of 10% NaOH is reacted at 20 ° C. for 5 hours. After completion of the reaction, 50 ml of water and 200 ml of toluene are added for extraction. After washing with water, the toluene layer is concentrated under reduced pressure. The residue is purified by silica gel column chromatography.

11.1 g of (-)-p-benzyloxy-1-phenethyl alcohol (V-13) are obtained.

Next, 1.14 g (5 mmol) of (V-13) was added to 10 m of pyridine.
and hexanoic acid chloride (0.74 g, 5.5 mmol) are added dropwise at 20 ° C. Further, it is kept at the same temperature for 2 hours and at 40 ° C. for 3 hours. Hereinafter, post-treatment and purification were carried out according to Example 1, and (-)-p-benzyloxy-
Hexanoate of 1-phenethyl alcohol (VII
-13) 1.57 g (96.5% yield) was obtained.

▲ [α] ²⁵ _D ▼ -67 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5281 Then, using 1.30 g (4 mmol) of (VII-13), debenzylation was carried out in the same manner as in Example 2. Reaction, post-treatment and purification.

0.86 g (yield 91%) of (-)-4- (1-hexanoyloxyethyl) phenol was obtained.

▲ [α] ²⁵ _D ▼ = −73 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5104

Claims (6)

(57) [Claims] 1. The compound of the general formula (I) (Wherein, R represents an alkyl group or an alkoxyalkyl group which may contain a halogen atom having 1 to 20 carbon atoms,
n is 1 or 2, and an asterisk denotes an asymmetric carbon. ) An optically active benzene derivative represented by 2. A compound of the general formula (VII) (Wherein, R, n and * represent the same meaning as described above,
A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom. A process for producing a benzene derivative represented by the general formula (I), wherein the optically active ester represented by the formula (1) is debenzylated by catalytic hydrogenation with hydrogen. 3. Formula (V) (Wherein, A, n and * represent the same meaning as described above) and an optically active alcohol represented by the general formula (VI) R-COOH (VI) (wherein, R represents the same meaning as described above) To obtain an optically active ester represented by the general formula (VII), and catalytically hydrogenating the optically active ester with hydrogen. A process for producing a benzene derivative represented by the general formula (I), wherein 4. A compound of the general formula (IV) (Wherein R ′, A and n have the same meanings as described above). Esterase having the ability to preferentially hydrolyze one of the optically active forms of the esters To obtain an optically active alcohol represented by the general formula (V), and then the optically active alcohol and an aliphatic carboxylic acid represented by the general formula (VI) or a derivative thereof And a method for producing an optically active benzene derivative represented by the general formula (I). 5. A compound of the general formula (III) (Wherein A and n have the same meanings as described above) by reacting an alcohol represented by the following formula with a lower alkylcarboxylic acid to obtain an ester represented by the general formula (IV). Asymmetric hydrolysis using an esterase having the ability to preferentially hydrolyze one of the optically active isomers to obtain an optically active alcohol represented by the general formula (V). A method for producing an optically active benzene derivative represented by the general formula (I), comprising reacting an alcohol with an aliphatic carboxylic acid represented by the general formula (VI) or a derivative thereof. 6. A compound of the general formula (II) (Wherein A and n have the same meanings as above) to obtain an alcohol represented by the general formula (III), and then the alcohol and a lower alkyl carboxylic acid To give an ester represented by the general formula (IV), followed by asymmetric hydrolysis using an esterase having the ability to preferentially hydrolyze one of the optically active forms of the ester. To obtain an optically active alcohol represented by the general formula (V), and then reacting the optically active alcohol with an aliphatic carboxylic acid or a derivative thereof represented by the general formula (VI). A method for producing an optically active benzene derivative represented by the general formula (I).