JP2508797B2 - 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): (In the formula, R represents an alkyl group or an alkoxyalkyl group having 1 to 20 carbon atoms and optionally containing a halogen atom.
Z represents a hydrogen atom or a halogen atom. * Indicates an asymmetric carbon atom) and an optically active benzene derivative and a method for producing the same.

The optically active benzene derivative represented by the general formula (I) is also used as an intermediate for medicines, agricultural chemicals and the like, and is particularly useful as a liquid crystal material as described below.

(Here, R ₁ represents an alkyl group, an alkoxyl group, etc., and Ar represents an aromatic group. R, Z and * have the same meanings as described above.) <Prior Art> Conventionally, such optically active benzene Nothing is known about the derivative, and of course no known method for its production.

<Problems to be Solved by the Invention> The present inventors have proposed such a novel 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.

<Means for Solving the Problems> The present invention relates to [First Step] General Formula (II) (In the formula, A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, or a halogen atom. Z has the same meaning as described above.) To reduce the ketone represented by the general formula (III) (Wherein A and Z have the same meanings as described above) [Second Step] The alcohols of the general formula (III) obtained in the first step are converted into lower alkylcarboxylic acids. By reacting with general formula (IV) (Wherein A and Z have the same meanings as described above, and R'represents a lower alkyl group) [Step 3] The general formula (IV) obtained in Step 2 The ester represented by the formula (V) is asymmetrically hydrolyzed using an esterase having the ability to hydrolyze any one of the optically active forms of the ester. (In the formula, A and Z have the same meanings as described above, and * indicates an asymmetric carbon atom.) Step of obtaining optically active alcohol [4th step] Obtained in 3rd step The optically active alcohol represented by the general formula (V) is represented by the general formula (VI) RX (VI) (wherein, R is an alkyl group having 1 to 20 carbon atoms and optionally containing a halogen atom). Alternatively, X represents a halogen atom or —OSO ₂ R ″, an alkoxyalkyl group.

Here, R ″ represents a lower alkyl group or an optionally substituted phenyl group) and is condensed with an alkylating agent represented by the general formula (VII) (In the formula, A, R, Z and * have the same meanings as described above.) Step of obtaining optically active ethers [fifth step] General formula (VII) obtained in the fourth step The optically active ethers are debenzylated to obtain the above-mentioned general formula (I)
In the step of obtaining an optically active benzene derivative represented by the following, respectively: 1st to 5th steps, 2nd to 5th steps,
It is a method for producing an optically active benzene derivative represented by the general formula (I), which comprises 3rd to 5th steps, 4th to 5th steps and 5th 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-
By reacting hydroxyacetophenones,
Can be easily obtained.

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 usually in the range of -30 to 100 ° C, preferably -20 to 90 ° C.

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.
Is not required to be isolated, and the reaction mixture may be directly used in the next step.

The reaction to obtain the ester (IV) from the alcohol (III) (second step) is carried out by reacting the alcohol (III) with a lower alkylcarboxylic acid to acylate.

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.
It 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 hydrogencarbonate, and organic acids or inorganic acids such as toluenesulfonic acid, methanesulfonic acid and sulfuric acid can 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.

When a lower alkyl carboxylic acid is used as the lower alkyl carboxylic acid, the ester is obtained by dehydration condensation in the presence of a condensing agent, the carboxylic acid being usually used in an amount of 1 to 2 equivalents with respect to the alcohol (III). (IV)
Can be obtained.

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

The amount of condensing agent used is 1 with respect to the lower alkylcarboxylic acid.
~ 1.2 equivalent times, and when an organic base is used, the amount used is 0.01 to 0.02 equivalent times with respect to the condensing agent.

The reaction temperature is usually −30 ° 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)
In the reaction (third step) to obtain 1), one of the optically active esters is hydrolyzed using an esterase having the ability to hydrolyze one of the optically active esters (asymmetric). Hydrolysis) is performed.

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.

The esterase in the present invention means an esterase in a broad sense including lipase.

Specific examples of such microorganisms include, for example, Enterobacter, Arthrobacter, Previbacterium, Cydudomonas, Alcaligenes, Micrococcus, Chromopacterium, Microbacterium, Corynebacterium. , Genus Bacillus, genus Lactobacillus, genus Trichoderma, genus Candida, genus Saccharomyces, genus Rhodotorula, genus Cryptococcus, genus Tolulopsis, genus Pichia, genus Penicillium, genus Aspergillus,
Microorganisms belonging to the genera Rhizopus, Mucor, Aureobasidium, Actinomucor, Nocardia, Streptomyces, Hansenula and Achromobacter are exemplified.

Cultivation of the above-mentioned microorganisms is usually carried out according to a conventional method, and for example, liquid culture can be performed to obtain a culture solution.

For example, sterilized liquid medium [malt extract / yeast extract medium for molds and yeasts (dissolve 5 g of peptone, 10 g of glucose, 3 g of malt extract, 3 g of yeast extract in 1 of water, p
H6.5), for bacteria, inoculated with microbial broth medium (dissolved glucose 10 g, peptone 5 g, meat extract 5 g NaCl3 g in water 1 to pH 7.2)] and inoculate the microorganism, usually at 20-40 ° C.
By performing reciprocal shaking culture for 1-3 days at
If necessary, solid culture may be performed.

Some of these esterases originating from microorganisms are commercially available and can be easily obtained. Specific examples of commercially available esterases include the followings.

Pseudomonas lipase [Lipase P (manufactured by Amano Pharmaceuticals)], Aspergillus lipase [Lipase AP (manufactured by Amano Pharmaceuticals)], Mucor lipase [Lipase M-AP]
(Manufactured by Amano Pharmaceutical Co., Ltd.)], lipase of Candida cylindrasse [lipase MY (manufactured by Meito Sangyo)], lipase of the genus Alcaligenes [lipase PL (manufactured by Meito Sangyo)], lipase of the genus Achromobacter [lipase AL (name) Made by Sugar Industry)],
Arthrobacter lipase [lipase-combined BSL (combined liquor refinement)], Chromobacterium lipase (manufactured by Toyo Brewing Co.), Rhizohus dermer lipase [Taripase (manufactured by Tanabe Seiyaku)], Rhizopus lipase [lipase Sai] Ken (Osaka Bacteria Research Institute)].

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

Steapsin, 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 usage forms thereof include a purified enzyme, a crude enzyme, an enzyme-containing material, a microbial culture solution, a culture, a bacterium, and a culture medium. It can be used in various forms such as a liquid and a product obtained by treating them as needed, and an enzyme and a microorganism can also be used in combination. Alternatively, it can also be used as an immobilized enzyme or immobilized bacterium immobilized on a resin or the like.

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 solution, 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 and sodium citrate, etc. is used, and the pH thereof is 8 to 11 in a culture solution of an alkaliphilic bacterium or alkaline esterase, A pH of 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 0.05 to 2M, preferably 0.05 to 0.5M.

The reaction temperature is usually 10 to 60 ° C., and the reaction time is generally 10 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) as hydrolysis products and optically active esters as hydrolysis residues [optically active compounds in raw material esters (IV) which were not hydrolyzed] Can be separated.

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 Pseudomonas layer or Arthrobacter layer is used as the lipase in this asymmetric hydrolysis reaction, optically active alcohols can be obtained with relatively high optical purity.

Also, during this hydrolysis, in addition to the buffer solution, toluene,
It is also possible to use an organic solvent inert to the reaction such as chloroform, methyl isobutyl ketone, or dichloromethane.
By using these, asymmetric hydrolysis can be advantageously performed.

The reaction for obtaining the optically active ethers (VII) from the optically active alcohols (V) (4th step) is performed by reacting the optically active alcohols (V) with an alkylating agent (VI).

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

The basic substance is required to be 1 equivalent or more with respect to the optically active alcohol, and the upper limit is not particularly limited, but it is preferably in the range of 1 to 5 equivalents.

The alkylating agent used in this reaction is a halide such as chloride, bromide or iodo having an alkyl group or an alkoxyalkyl group which may include a halogen atom having 1 to 20 carbon atoms as exemplified below. Alternatively, they are sulfuric acid esters (methanesulfonic acid ester, ethanesulfonic acid ester, benzenesulfonic acid ester, toluenesulfonic acid ester, etc.). These alkylating agents can be easily synthesized from the corresponding alcohol, if necessary.

Methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, totadecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxy. Butyl, methoxypentyl, methoxyhexyl, methoxyheptyl, methoxyoctyl, methoxynonyl, methoxydecyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, ethoxyheptyl, ethoxyoctyl, ethoxynonyl, ethoxydecyl, Propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl, propoxyhex Le, propoxy octyl, propoxy decyl, butoxymethyl, butoxyethyl, butoxypropyl, butoxybutyl, Butokishipenchiru, Butokishihekishiru, Butokishihepuchiru, Butokishinoniru,
Pentyloxymethyl, pentyloxyethyl, pentyloxypropyl, pentyloxybutyl, pentyloxypentyl, pentyloxyoctyl, pentyloxydecyl, hexyloxymethyl, hexyloxyethyl, hexyloxypropyl, hexyloxybutyl,
Hexylhexylpentyl, hexyloxyhexyl, hexyloxyoctyl, hexyloxynonyl, hexyloxydecyl, heptyloxymethyl, heptyloxyethyl, heptyloxypropyl, heptyloxypentyl, octyloxymethyl, octyloxyethyl, decyloxymethyl, decyl Oxyethyl, decyloxypropyl, 2-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, 2-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 and 2-halooctyl (however, halo in the above alkyl group represents fluorine, chlorine, bromine or iodine).

The alkyl group or alkoxyalkyl group which may contain a halogen atom having 1 to 20 carbon atoms may be an optically active group.

The alkylating agent (halide or sulfate ester) having these optically active groups is synthesized from the corresponding optically active alcohol as necessary. Some of the optically active alcohols are easily obtained by asymmetric reduction of the corresponding ketone with an asymmetric metal catalyst, a microorganism or an enzyme. Others can be derived from optically active amino acids and optically active oxyacids that occur naturally or are obtained by resolution, such as: Valine, leucine, isoleucine, phenylalanine, threonine, arosreonine, homoserine, alloisoleucine, tert-leucine,
2-aminobutyric acid, norvaline, norleucine, ornithine, lysine, hydroxylysine, phenylglycine, aspartic acid, glutamic acid, mandelic acid, tropic acid,
3-hydroxybutyric acid, malic acid, tartaric acid, isopropylmalic acid, etc.

The amount of such an alkylating agent to be used may be 1 equivalent or more relative to the optically active alcohol (V), but is usually in the range of 1 to 5 equivalents.

As the reaction solvent, a polar solvent such as dimethyl sulfoxide, hexamethylphosphorylamide, N-methylpyrrolidone and the like can be used in addition to the solvents exemplified in the second step.

The reaction temperature is generally -50 ° C to 120 ° C, preferably -30 ° C.
The range is up to 100 ° C.

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

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 under normal or elevated hydrogen pressure, and the amount of absorbed hydrogen is the optically active ether (VII) as a raw material.
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 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.

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

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

Example 1 180.9 g (0.8 mol) of 4-benzyloxyacetophenone (II-1), 300 ml of tetrahydrofuran and 200 ml of methanol were placed in a four-necked flask equipped with a stirrer and a thermometer.
30.28 g (0.8 mol) of sodium borohydride is added thereto at 15 to 25 ° C. over 2 hours. After keeping it at the same temperature for 5 hours, it is poured into ice water and extracted twice with 1000 ml of ethyl acetate. The organic layer was concentrated under reduced pressure and 4-benzyloxy 1-phenethyl alcohol (III-1) 177.0 g
(Yield 97%) was obtained.

Next, 136.88 g (0.6 mol) of (III-1) obtained here was dissolved in a mixed liquid of 600 ml of toluene and 100 ml of pyridine, and 51.82 g (0.66 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 ℃ for 2 hours. After the reaction is completed, cool to 10 ° C or less,
Add 400 ml of water. The separated organic layer was washed with 2N aqueous hydrochloric acid, water,
The extract was washed successively with 5% sodium carbonate and water, concentrated under reduced pressure, and purified by column chromatography to give 4-benzyloxy-1-phenethyl alcohol acetate (IV-
1) 159.6 g (yield 98.5%) was obtained.

Next, 135.0 g (0.5 mol) of (IV-1) obtained above is vigorously stirred with 1500 ml of 0.3 M phosphate buffer (pH 7.5) and 13.5 g of amanolipase "P" at 40 to 45 ° C for 40 hours. After completion of the reaction, the reaction mixture was extracted with 1000 ml of ethyl acetate, the organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a toluene: ethyl acetate (5: 2) mixture as an elution solvent, (+). -4-benzyloxy-1-phenethyl alcohol [V-1] 46.76 g (41% yield) [▲
[Α] _{20 D} ▼ + 35.9 ° (c = 1, CHCl ₃ ), mp66-68
° C], and unreacted ester 37, 48 g [▲ [α] _{20 D} ▼-
93 ° (c = 1, CHCl ₃ ), mp 52-55 ° C.].

Then, a solution of 3.42 g (0.015 mol) of [V-1] obtained here and 40 ml of dimethylformamide was cooled to 10 ° C, 0.47 g (0.0196 mol) of sodium hydride was added, and the mixture was stirred at 30 to 35 ° C for 1
Insulate for hours. Next, n-propyl tosylate 4.82 g (0.0
225 mol) is added at 20 to 25 ° C, and the mixture is reacted at 30 to 40 ° C for 5 hours. After completion of the reaction, the reaction mixture is poured into ice and extracted with 100 ml of ethyl acetate. The organic layer is washed with water and then concentrated under reduced pressure. The concentrated residue was purified by column chromatography, and (+)-4-benzyloxy-1- (1 '
-Propoxyethyl) benzene (VII-1) 3.81 g (yield 94
%) Was obtained. [▲ [α] _{20 D} ▼ + 70.8 ° (c = 1, CHC
l ₃ ), mp 51-53 ° C.] Next, 3.51 g (0.013 mol) of (VII-1) obtained here was mixed with 10 ml of methanol and 0.2 g of 5% Pd-carbon, and the mixture was mixed under a hydrogen atmosphere at atmospheric pressure. Contact hydrogenation. When the amount of absorbed hydrogen reaches 300 ml, stop the reaction and remove the catalyst separately. The liquid was concentrated and the residue was purified by column chromatography using a toluene-ethyl acetate (5: 2) mixture as an eluent to obtain (+)-4- (1'-propoxyethyl) phenol.
2.18 g (93%) was obtained. [▲ [α] _{20 D} ▼ + 85.6 ° (c =
1, CHCl ₃ ), mp 61-63 ° C.] Example 2 3.42 g (0.015 mol) of [V-1] obtained in Example 1 and N-
A solution of 30 ml of methylpyrrolidone is cooled to 5 ° C. and 0.72 g (0.03 mol) of sodium hydride are added. After that, the temperature is kept at 30 to 35 ° C for 1 hour. Then methyl iodide
5.32 g (0.0375 mol) is added at 15 to 20 ° C, and the mixture is reacted at 20 to 30 ° C for 2 hours and further at 40 to 50 ° C for 2 hours. After completion of the reaction, the reaction mixture is poured on ice and extracted with 50 ml of ethyl acetate. Then, purification treatment is carried out according to Example 1 (+)-
4-Benzyloxy-1- (1'-methoxyethyl) benzene (VII-2) (3.49 g, yield 96%) was obtained. [▲ [α]
_{20 D} ▼ + 77.6 ° (c = 1, CHCl ₃ ), ▲ n ²⁰ _D ▼ 1.5432] Next, 2.42 g (0.01 mol) of (VII-2) obtained here was dissolved in 15 ml of tetrahydrofuran and 0.2% of 5% Pd-carbon. Mix with g and contact hydrogenate under atmospheric pressure at atmospheric pressure. Hydrogen absorption capacity is 240m
Stop the reaction at l and remove the catalyst separately. The liquid was concentrated and the residue was further purified by column chromatography to give (+)-4- (1'-methoxyethyl) phenol 1.48.
g (98% yield) was obtained.

[▲ [α] _{20 D} ▼ + 106.1 ° (c = 1, CHCl ₃ ), mp114
~ 115 ° C] Example 3 A solution of 3.42 g (0.015 mol) of [V-1] obtained in Example 1 and 40 ml of dimethylformamide was cooled to 10 ° C.
To this, 0.47 g (0.0196 mol) of sodium hydride was added, and 3
Incubate at 0-35 ° C for 1 hour. After that, 5.76 g (0.0225 mol) of n-hexyl tosylate is added, and the mixture is reacted at 40 to 45 ° C for 5 hours. After completion of the reaction, post-treatment was carried out according to Example 1 to obtain 4.42 g of (+)-4-benzyloxy-1- (1'-n-hexyloxyethyl) benzene (VII-3) (yield 94.5).
%) Was obtained. [▲ [α] _{20 D} ▼ + 58.9 ° (c = 1, CHC
l ₃ ), ▲ n ²⁰ _D ▼ 1.5230] Next, 3.12 g (0.01 mol) of (VII-3) obtained here was mixed with 15 ml of methanol and 0.3 g of 5% Pd-carbon, and the mixture was heated to normal pressure under a hydrogen atmosphere. Contact hydrogenate. When the hydrogen absorption is 240 ml, stop the reaction and remove the catalyst separately. Concentrate the liquid,
The residue was purified by column chromatography to obtain (+)-4- (1 '
2.13 g of -n-hexyloxyethyl) phenol (yield 9
6%). [▲ [α] _{20 D} ▼ + 72.5 ° (c = 1, CHCl
₃ ), ▲ n ²⁰ _D ▼ 1.5060] Examples 4 to 8 and 10 Reaction and post-treatment were carried out according to Example 3 except that n-hexyl tosylate was replaced with the alkylating agent shown in Table 1,
The results shown in the table were obtained.

Example 9 Unreacted ester 1 obtained in the asymmetric hydrolysis process of Example 1
3.5 g (50 mmol) are stirred for 2 hours at 30-40 ° C. in a mixture of 50 ml of methanol, 30 ml of 20% sodium hydroxide and 30 ml of tetrahydrofuran. After the reaction was completed, 200 ml of water was added to the reaction mixture, and the pH was adjusted to 6 with 4N hydrochloric acid water, and then ether 50 was added.
Extract with 0 ml. After washing the organic layer with water, the solvent was distilled off under reduced pressure to obtain (-)-4-benzyloxy-1- as a white solid.
11.2 g (yield 98%) of phenethyl alcohol was obtained.

3.42 g (15 mmol) of this alcohol was subjected to an alkylation reaction, post-treatment and purification according to Example 3 except that (S) -2-methylbutyl tosylate was used instead of n-hexyl tosylate ( 4.02 g (yield 91%) of-)-4-benzyloxy-1- (1 '-(S) -2-methylbutyloxyethyl) benzene (VII-9) was obtained.

Melting point 46.5 to 47.5 ° C, ▲ [α] _{20 D} ▼ -48.2 ° (c =
1, CHCl ₃ ) Next, (VII-9) obtained here was subjected to catalytic hydrogenation reaction, post-treatment and purification according to Example 3 to obtain (−)-(1- (S)).
-2-Methylbutyloxyethyl) benzene (I-9)
2.0 g (yield 96%) was obtained. ▲ n ²⁰ _D ▼ 1.5101, ▲ 〔α〕 _20
D ▼ -71.5 ° (c = 1, CHCl ₃ ) Example 11 In the same apparatus as in Example 1, 24.0 g (0.1 mol) of 4- (4-methylbenzyloxy) acetophenone (II-11), 100 ml of chloroform and methanol were added. 30 ml was charged, and 4.5 g (0.12 mol) of sodium borohydride was added thereto at 15 to 20 ° C over 2 hours. After stirring at the same temperature for 5 hours, the reaction mixture is poured into ice water and extracted with chloroform. The organic layer was concentrated under reduced pressure to give 4- (4-methylbenzyloxy) -1-phenethyl alcohol (III-11) 23.1
g (yield 95.5%) was obtained.

Next, 18.16 g (0.075 mol) of (III-11) obtained here,
Dichloromethane 100 ml and 4-pyrrolidinopyridine 0.5
To a mixture of g are added 16.7 g (82.5 mmol) N, N'-dicyclohexylcarbodiimide and 5.0 g (82.5 mmol) acetic acid. After stirring at room temperature for 10 hours, the white precipitate was separated and the solution was washed successively with water, 5% acetic acid, water and 5% aqueous sodium hydrogen carbonate. Hereinafter, the post-treatment and purification were carried out according to Example 1 and 4
20.78 g (yield 97.5%) of acetic ester (IV-11) of-(4-methylbenzyloxy) -1-phenethyl alcohol
I got

Next, 19.2 g (70 mmol) of this (IV-11) was added to 200 ml of 0.3M phosphate buffer (pH 7.0) and amanolipase "P".
Stir vigorously with 2.88g for 20 hours at 35-40 ° C. After completion of the reaction, post-treatment and purification were carried out according to Example 1 (+).
6.6 g (yield 39%) of 4- (4-methylbenzyloxy) -1-phenethyl alcohol (V-11) was obtained. Melting point 52 ~
53 ° C, ▲ [α] _{20 D} ▼ + 34.2 ° (c = 1, CHCl ₃ ) Next, 1.2 g (0.005 mol) of (V-11) obtained here and N-
A solution consisting of 20 ml of methylpyrrolidone is cooled to 10 ° C,
To this, add 0.17 g (0.007 mol) of sodium hydride, and add 30
Incubate at ~ 35 ° C for 1 hour. After that, 1.7 g (0.007 mol) of (S) -2-chloropropyl tosylate was added to 40-45
React at 4 ° C for 4 hours. After completion of the reaction, the reaction mixture is poured into ice water and extracted with 200 ml of toluene. The organic layer is washed with water and then concentrated under reduced pressure. The concentrated residue is purified by silica gel column chromatography, (+)-4
-(4-Methylbenzyloxy) -1- {1'-
1.38 g (yield 92%) of ((S) -2-chloropropoxy) ethyl} benzene (VII-11) was obtained. ▲ [α] _{20 D} ▼ ＝
+ 73.8 ° (c = 1, CHCl ₃ ) Melting point 42-44 ° C. Then, 1.0 g of (VII-11) obtained here was mixed with 20 ml of methanol and 0.1 g of 5% Pd-carbon, and the mixture was placed under a hydrogen atmosphere. Contact hydrogenation at atmospheric pressure. When the hydrogen absorption reaches the equivalence point, the reaction is stopped and the catalyst is removed separately. The solution was concentrated, and the residue was purified by column chromatography using a toluene-ethyl acetate mixed solution as an eluting solvent to obtain (+)-4- {1-.
((S) -2-chloropropoxy) ethyl} phenol
0.56 g (84% yield) was obtained.

▲ [α] _{20 D} ▼ + 93 ° (c = 1, CHCl ₃ ), melting point 50-51 ° C. Example 12 4- (4-methoxybenzyloxy) acetophenone (instead of 4- (4-methylbenzyloxy) acetophenone II-12) Reduction reaction and post-treatment were conducted according to Example 11 except that 25.6 g (0.1 mol) was used to collect 4- (4-methoxybenzyloxy) -1-phenethyl alcohol (III-12). The rate was 97%.

Next, 0.075 mol of this (III-12) was added to 4- (4-methylbenzyloxy) -1-phenethyl alcohol (III-
Acylation reaction, post-treatment and purification were conducted in the same manner as in Example 11 except that the acetic acid ester of 4- (4-methoxybenzyloxy) -1-phenethyl alcohol (IV-12) was collected. Obtained at a rate of 96%.

Next, in place of 4- (4-methylbenzyloxy) -1-phenethyl alcohol acetate (IV-11),
Asymmetric hydrolysis reaction, post-treatment and purification were conducted in the same manner as in Example 11 except that the above (IV-12) was used to obtain (+)-4- (4-methoxybenzyloxy) -1-phenethyl alcohol (V-12). ) Was obtained with a yield of 35%.

1.29 g (0.005 mol) of (V-12) obtained here was added to (S)-
Example 1 except that 2.8 g (0.008 mol) of n-octadecyl bromide was used instead of 2-chloropropyl tosylate.
Alkylation reaction and post-treatment in the same manner as in (1) -4
2.3 g of-(4-methoxybenzyloxy) -1- (1-octadecyloxyethyl) benzene (VII-12) (yield 90
%) Was obtained.

1.0 g of (VII-12) obtained above was subjected to catalytic hydrogenation reaction, post-treatment and purification in the same manner as in Example 10 to give (+)-4- (1-octadecyloxyethyl) phenol 0.73 g (yield 89% )
I got

▲ [α] _{20 D} ▼ + 31.1 ° (c = 1, CHCl ₃ ), ▲ n ²⁰ _D ▼ 1.
4990 Example 13 2-Fluoro-4-benzyloxyacetophenone (II-13) 2 was added to a 4-necked flask equipped with a stirrer and a thermometer.
4.4 g (0.1 mol) and 300 ml of ethanol are charged, and 3.8 g (0.1 mol) of sodium borohydride is added thereto at 15 to 25 ° C over 10 minutes. After keeping the same temperature for 5 hours,
Pour into ice water and extract with 500 ml of ethyl acetate. The organic layer is washed well with water and then concentrated under reduced pressure to give 2-fluoro-
4-benzyloxy-1-phenethyl alcohol (III-
13) 24.0 g was obtained.

Next, 19,7 g (0.08 mol) of (III-13) obtained here was dissolved in 200 ml of pyridine, and 12.2 g of acetic anhydride was added thereto at 30 to 40 ° C.
It is dripped at, and it heat-retains at 40-50 degreeC for 6 hours. After the reaction,
400 ml of water was added, and the separated organic layer was 2N-hydrochloric acid, water, 5%
The extract was washed successively with aqueous sodium hydrogen carbonate and water and concentrated under reduced pressure to give 22.6 g (yield 98%) of acetic ester (IV-13) of 2-fluoro-4-benzyloxy-1-phenethyl alcohol.

Next, 20 g (0.07 mol) of (IV-13) obtained above is vigorously stirred at 38-40 ° C for one day together with 500 ml of 0.3 M phosphate buffer (pH 7.0) and 3 g of Arthrobacter lipase. After completion of the reaction, the reaction mixture was extracted with 500 ml of ethyl acetate, the organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a toluene: ethyl acetate mixed solution as an eluent.
8.32 g (yield 48%) of (+)-2-fluoro-4-benzyloxy-1-phenethyl alcohol (V-13) was obtained.

▲ [α] _{20 D} ▼ + 29.6 ° (c = 1, CHCl ₃ ), white oily substance. Subsequent to (+)-4-benzyloxy-1-phenethyl alcohol (V-1), obtained as above. (V-13) 3.
The alkylation reaction and post-treatment were carried out in the same manner as in Example 3 except that 69 g (0.015 mol) was used, and (+)-2-fluoro-4-
4.55 g (yield 92%) of benzyloxy-1- (1'-n-hexyloxyethyl) benzene (VII-13) was obtained. ▲
[Α] _{20 D} ▼ + 53.8 ° (c = 1, CHCl ₃ ), ▲ n ²⁰ _D ▼ 1.51
62 Next, (VII-13) obtained here was subjected to catalytic hydrogenation reaction, post-treatment and purification in the same manner as in Example 3 to give (+)-3-fluoro-4- (1′-n-hexyloxyethyl). ) Phenol (I-13) was obtained with a yield of 89%. ▲ 〔α〕 _{20 D} ▼ ＋ 72.2 °
(C = 1, CHCl ₃ ), ▲ n ²⁰ _D ▼ 1.4708 Example 14 Except that 2-chloro-4-benzyloxyacetophenone (II-14) was used instead of 2-fluoro-4-benzyloxyacetophenone. Reduction, acylation and asymmetric hydrolytic reaction, post-treatment and purification were carried out in the same manner as in Example 13 to obtain 7.9 g of (+)-2-chloro-4-benzyloxy-1-phenethyl alcohol (V-14). ▲ ［α］ _{20 D} ▼ ＋ 3
3.2 ° (c = 1, CHCl ₃ ), ▲ n ²⁰ _D ▼ 1.5775 Then, in place of (+)-4-benzyloxy-1-phenethyl alcohol (V-1), the above (V-14) 3.95 g.
(+)-2-chloro-4-benzyloxy-1- (1′-n-hexyloxyethyl) benzene (VII) was subjected to the alkylation reaction and post-treatment in the same manner as in Example 3 except that (0.015 mol) was used. -14) 4.73 g (yield 91%) was obtained. ▲
[Α] _{20 D} ▼ + 51.3 ° (c = 1, CHCl ₃ ), ▲ n ²⁰ _D ▼ 1.53
26 Next, (VII-14) obtained here was subjected to catalytic hydrogenation reaction, post-treatment and purification in the same manner as in Example 3 to give (+)-3-chloro-
4- (1'-n-hexyloxyethyl) phenol (I-14) was obtained with a yield of 87%. ▲ 〔α〕 _{20 D} ▼ ＋ 75.3 °
(C = 1, CHCl ₃ ) ▲ n ²⁰ _D ▼ 1.4935 Example 15 In place of 4-benzyloxyacetophenone, 4-
If reduction, acylation, asymmetric hydrolysis, alkylation and catalytic hydrogenation reaction, post-treatment and purification are carried out in the same manner as in Example 1 except that (4-chlorobenzyloxy) acetophenone is used, (+)-4- (1 -Propoxyethyl) phenol can be obtained.

Claims (6)

(57) [Claims] 1. A general formula (In the formula, R represents an alkyl group or an alkoxyalkyl group having 1 to 20 carbon atoms and optionally containing a halogen atom.
Z represents a hydrogen atom or a halogen atom. ) Optically active benzene derivative 2. General formula (Wherein, R represents an alkyl group or an alkoxyalkyl group which may contain a halogen atom having 1 to 20 carbon atoms,
Z represents a hydrogen atom or a halogen atom. A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom. (* Indicates an asymmetric carbon atom) The general formula characterized by debenzylating an optically active ether derivative represented by (In the formula, R, Z and * have the same meaning as described above.) A method for producing an optically active benzene derivative 3. General formula (In the formula, A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, or a halogen atom. Z represents a hydrogen atom or a halogen atom. * Indicates an asymmetric carbon atom.) Optical activity And an alcohol of the general formula R—X (wherein R represents an alkyl group or an alkoxyalkyl group having 1 to 20 carbon atoms and optionally containing a halogen atom, and X represents a halogen atom or —OSO ₂ R ″). Where R ″ represents a lower alkyl group or a substituted phenyl group) and is condensed with an alkylating agent represented by the general formula (In the formula, R, A, Z and * have the same meanings as described above.) The method for producing an optically active benzene derivative according to claim 2, wherein an optically active ether is obtained. 4. A general formula (Wherein A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom, Z represents a hydrogen atom or a halogen atom, and R'represents a lower alkyl group). Asymmetric hydrolysis using an esterase having the ability to hydrolyze any one of the optically active compounds of the general formula (In the formula, A and Z have the same meanings as described above, and * indicates an asymmetric carbon atom.) The optically active benzene derivative according to claim 3, which is obtained. Manufacturing method. 5. A general formula (Wherein A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom. Z represents a hydrogen atom or a halogen atom), and the alcohol represented by the general formula is reacted with a lower alkylcarboxylic acid. The method for producing an optically active benzene derivative according to claim 4, wherein an ester represented by the formula: wherein A and Z have the same meanings as described above and R ′ represents a lower alkyl group. 6. A general formula (In the formula, A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group or a halogen atom. Z represents a hydrogen atom or a halogen atom). (In the formula, A and Z have the same meanings as described above) The method for producing an optically active benzene derivative according to claim 5, wherein an alcohol represented by