JP2590517B2 - 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 which may contain a halogen atom having 1 to 20 carbon atoms, and A represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms or an alkoxyl group.
n is 1 or 2, and * indicates that it is an asymmetric carbon. ) And an optically active benzene derivative represented by the formula:

<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 known at all. Not.

<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.

For example, the optically active benzene derivative can be led to a novel liquid crystal compound by a method represented by the following formula, and the compound has very excellent properties as a ferroelectric liquid crystal.

(In the formula, Ar represents an aromatic group, R ″ represents an alkyl group or an alkoxyl group, and 1 is 1 or 2.
R, n and * have the same meaning as described above. <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 optically active benzene derivative represented by the general formula (I) has a general formula (II) (Wherein, A, n and * have the same meanings as described above) and an optically active alcohol represented by the general formula (III): R—COOH (III) (wherein, R represents 1 to 1 carbon atoms) And an alkyl group which may contain 20 halogen atoms.) An aliphatic carboxylic acid or a derivative thereof represented by the following formula:

Examples of the aliphatic carboxylic acid represented by the general formula (III) include the following carboxylic acids.

Acetic acid, propionic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid,
Undecanoic acid, dodecanoic acid, tridecanoic acid, tetradecanoic acid, pentadecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, nonadecanoic acid, eicosanoic acid, isolacic acid, 2-methylbutanoic acid, 2,3-dimethylbutanoic acid, 2,3, 3-trimitylbutanoic acid, 2-methylpentanoic acid, 3-methylpentanoic acid, 2,3-dimethylpentanoic acid, 2,4-dimethylpentanoic acid, 2,3,3,4-tetramethylpentanoic acid, 2- Methylhexanoic acid, 3-methylhexanoic acid, 4-methylhexanoic acid, 2,5-dimethylhexanoic acid, 2-methylheptanoic acid, 2-methyloctanoic acid, 2
-Trihalomethylpentanoic acid, 2-trihalomethylhexanoic acid, 2-trihalomethylheptanoic acid, 2-halopropanoic acid, 3-halo-2-methylpropanoic acid, 2,3-dihalopropanoic acid, 2-halobutanoic acid, 3-halobutanoic acid,
2,3-dihalobutanoic acid, 2,4-dihalobutanoic acid, 3,4-dihalobutanoic acid, 2-halo-3-methylbutanoic acid, 2-halo-3,3-dimethylbutanoic acid, 2-halopentanoic acid,
-Halopentanoic acid, 4-halopentanoic acid, 2,4-dihalopentanoic acid, 2,5-dihalopentanoic acid, 2-halo-3-
Methylpentanoic acid, 2-halo-4-methylpentanoic acid,
2-halo-3-monohalomethyl-4-methylpentanoic acid, 2-halohexanoic acid, 3-halohexanoic acid, 4-halohexanoic acid, 5-halohexanoic acid, 2-haloheptanoic acid, 2-halooctanoic acid (provided that halo and Is
Represents fluorine, chlorine, bromine or iodine. ).

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, tropic acid, 3-hydroxybutyric acid, malic acid, tartaric acid, isopropylmalic acid and the like.

The reaction between such an optically active alcohol compound (II) and an aliphatic carboxylic acid or a derivative thereof is generally carried out 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 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 1 equivalent or more times with respect to the optically active alcohol compound (II). 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 in the presence of a condensing agent by using 1 to 2 equivalent times of the optically active alcohol (II). An optically active benzene derivative (I) 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 −30 to 100 ° C., preferably −2 to 100 ° C.
5 ° C to 80 ° C.

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,
The target optically active benzene derivative represented by the general formula (I) can be isolated from the reaction mixture by concentration, distillation, or the like, and can be purified by column chromatography or the like, if necessary.

Optically active alcohols (II) have the general formula (IV) (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 obtained by asymmetric hydrolysis using a capable esterase.

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, Aureobasidium, Actinomucor, Nocardia, Streptomyces, Hansenula and Achromobacter are exemplified.

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

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;
H6.5), for bacteria, inoculated with microorganisms in a sweetened 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)]. 40
The culture is performed by reciprocating shaking culture at 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 [Lipase P (manufactured by Amano Pharmaceutical)], Aspergillus lipase [Lipase AP (manufactured by Amano Pharmaceutical)], Mucor lipase AP (manufactured by Amano Pharmaceutical), lipase of Candida syrindrasse [lipase MY (name Sugar industry)], lipase of the genus Alcaligenes [lipase PL (manufactured by Meito Sangyo)], lipase of the genus Achromobacter [lipase AL (manufactured by Meito Sangyo)], lipase of the genus Arthrobacter (manufactured by Nippon Chemical) Lipase of the genus Chromobacterium (manufactured by Toyo Brewery), lipase of Rhizofus delemar [Talipase (manufactured by Tanabe Seiyaku)], and lipase of the genus Rhizobus [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 enzyme or microorganism in a buffer solution.

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 (II) which are hydrolysis products and optically active esters which remain as a hydrolysis residue according to the methods described above, etc. [Of the optically active compounds in raw material esters (IV), those which have not been hydrolyzed] Can be separated.

The optically active esters obtained here are further hydrolyzed if necessary, and the optically active alcohols (I
I) may be enantiomeric optically active alcohols.

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

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.

Esters (IV) have the general formula (V) (Wherein, A and n have the same meanings as described above). The alcohol can be produced by reacting a lower alkyl carboxylic acid with an alcohol represented by the formula:

In this reaction (acylation), an acid anhydride or 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, valeyl chloride or bromide and the like.

In this reaction, the amount of the lower alkyl carboxylic acid used must be at least one equivalent times the alcohol (V), and the upper limit is not particularly limited.
Equivalent times.

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 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 time when the alcohol (V) as the raw material 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.

Alcohols (V) have the general formula (VI) (Wherein, A and n have the same meanings as described above).

The reduction of ketones (VI) 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. The amount of the reducing agent used is at least 1 equivalent equivalent to the amount of the starting ketones, and is usually 1 to 10 equivalents. Range of double.

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 (V) 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 (V) in order to obtain the esters (IV) in the next step, and the reaction mixture may proceed to the next step.

The ketones (VI) as starting materials can be easily obtained, for example, by reacting benzyl halides and acetylphenols as shown below.

<Effect of the Invention> According to the method of the present invention, an optically active benzene derivative (I), which is a novel compound, can be obtained at a high yield. It can be used not only as an intermediate but also as an intermediate of an organic electronic material such as a liquid crystal compound.

<Examples> Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these 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), 300 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 (0.3 mol) of the obtained (III-1) was dissolved in a mixture of 300 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 (p, 7.5) and 6.75 g of amanolipase “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 ), mp 66-68
° C), and 37.4 g of unreacted ester [▲ [α] ²⁰ _D ▼ -93
゜ (c = 1, CHCl ₃ ), mp 52-55 ° 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 (+)-
1.39 g (98% yield) of propionic acid ester (1-1) of p-benzyloxy-1-phenethyl alcohol was obtained. This was further purified by recrystallization using ethanol.

[▲ [α] ²⁵ _D ▼ = + 89 ° (c = 1, CHCl ₃ ) Melting point 48 ° C. Example 2 (+)-p-benzyloxy-1-phenethyl alcohol (V-1) 1.14 obtained in Example 1 g (5 mmol),
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 with 20 ml of toluene. Thereafter, washing is performed sequentially with 1N-hydrochloric acid aqueous solution, 2% aqueous sodium bicarbonate and water. Thereafter, post-treatment and purification were performed according to Example 1,
1.58 g (97% yield) of a hexanoic acid ester of (+)-p-benzyloxy-1-phenethyl alcohol was obtained.

▲ [α] ²⁵ _D ▼ +73 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5289 Example 3 4′- placed in a four-necked flask equipped with a stirrer and a thermometer.
Acetyl-4-benzyloxybiphenyl (II-2) 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 was concentrated under reduced pressure to obtain 11.74 g (yield 96.5%) of 4-benzyloxy-4 '-(1-hydroxyethyl) biphenyl (III-2).

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 acetic acid ester (IV-2) of 4 '-(1-hydroxyethyl) biphenyl was obtained.

8.65 g (0.02 g) of the 4-benzyloxy-4 '-(1-hydroxyethyl) biphenyl acetate (IV-2)
25 mol) is mixed with 200 ml of 0.3 M phosphate buffer (pH 7.5) and 5 g of Amano lipase “P” and stirred vigorously at 40-45 ° C. for 120 hours. After completion of the reaction, the reaction mixture is
Extract with 100ml. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a mixture of toluene: ethyl acetate = 5: 2 as an eluent to give (+)-4-benzyloxy-4 '-(1-hydroxyethyl) biphenyl 2.89. g
(V-2) [▲ [α] ²⁰ _D ▼ + 34.8 ゜ (c = 1, CHC
l _3), to obtain a mp158~159 ℃].

Next, 1.22 g (4 mmol) of (V-2) 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 washed successively with 1N aqueous hydrochloric acid, 2% aqueous sodium bicarbonate and water. The organic layer is concentrated and then purified by silica gel column chromatography. 1.64 g of octanoic acid ester of (+)-4-benzyloxy-4 '-(1-hydroxyethyl) biphenyl
(95.5% yield).

▲ [α] ²⁵ _D ▼ + 43 ° (c = 1, CHCl ₃ ) Melting point 92-93 ° C. Example 4 (+)-4-benzyloxy-4′- obtained in Example 3
1.22 g of (1-hydroxyethyl) biphenyl (V-2)
(4 mmol), 0.72 g (4.8 mmol) of (2S, 3S) -2-chloro-3-methylpentanoic acid and dichloromethane
Dicyclohexylcarbodiimide in a solution consisting of 20 ml
0.91 g (4.4 mmol) and 4-pyrrolidinopyridine 0.
Add 03g and react at room temperature for 10 hours. After the reaction,
The precipitated 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).
1.68 g (95.5% yield) of (2S, 3S) -2-chloro-3-methylpentanoic acid ester of (+)-4-benzyloxy-4 '-(1-hydroxyethyl) biphenyl was obtained.

▲ [α] ²⁵ _D ▼ +68.3 ゜ (c = 1, CHCl ₃ ) Melting point 125-126 ° C. Example 5 In a flask similar to that used in Example 1, 4- (p-methylbenzyloxy) acetophenone (II- 3) 24.0g
(0.1 mol), chloroform 100 ml and methanol 30 ml
And sodium borohydride at 15-20 ° C
4.5 g (0.12 mol) are added in 2 hours. After keeping at the same temperature for 5 hours, the mixture is extracted into chloroform in ice water. The organic layer was concentrated under reduced pressure to give p- (4-methylbenzyloxy) -1-phenethyl alcohol (III-3) 23.
1 g (95.5% yield) was obtained.

Next, to a mixed solution of 18.16 g (0.075 mol) of (III-3) obtained above, 100 ml of toluene and 15 ml of pyridine,
6.48 g (82.5 mmol) of acetyl chloride are added over 2 hours at 10-20 ° C. After keeping at the same temperature for 1 hour, 40 ~
Incubate at 50 ° C for another 2 hours. The post-treatment and purification were carried out in the same manner as in Example 1 to obtain p- (4-methylbenzyloxy) -1-phenethyl alcohol acetate (IV-
3) 20.78 g (97.5% yield) was obtained.

Next, 19.2 g (70 mmol) of (IV-3) 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 asymmetric hydrolysis reaction, post-treatment and purification are carried out according to Example 1.

6.6 g of (+)-p- (4-methylbenzyloxy) -1-phenethyl alcohol (V-3) (39% yield)
[Α] ²⁰ _D ▼ + 34.2 ゜ (c = 1, CHCl ₃ ), melting point 52-53
° C]. Next, 1.21 g (5 mmol) of (V-3) obtained here was converted to 1.65 g (6 mmol) of palmitic acid chloride,
1 at 25-30 ° C with 10m of pyridine and 10ml of toluene
Let react for 0 hours. After the completion of the acylation reaction, post-treatment and purification are performed according to Example 1.

2.16 g (90% yield) of palmitic acid ester of (+)-p- (4-methylbenzyloxy) -1-phenethyl alcohol was obtained.

▲ [α] ²⁵ _D ▼ +58 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5186 Example 6 4- (p-methoxybenzyloxy) acetophenone in place of 4- (p-methylbenzyloxy) acetophenone (II-4) A reduction reaction is carried out in the same manner as in Example 1 except that 25.6 g (0.1 mol) is used. p- (4-methoxybenzyloxy) -1-phenethyl alcohol (III-
Obtain 4).

Next, 0.075 mol of (III-4) was reacted, worked up and purified in the same manner as in the acylation reaction of Example 5 to give p- (4-methoxybenzyloxy) -1-phenethyl alcohol acetate (IV- Obtain 4).

Next, (IV-4) is subjected to asymmetric hydrolysis in the same manner as in Example 5, and further post-treated and purified. (+)-P- (4-methoxybenzyloxy) -1-phenethyl alcohol (V
-4) is obtained.

By subjecting this (V-4) to an acylation reaction, post-treatment and purification in the same moles as in Example 5 except that decanoic acid chloride was used instead of palmitic acid chloride,
A decanoic acid ester of (+)-p- (p-methoxybedyloxy) -1-phenethyl alcohol is obtained.

Example 7 As in Example 3, except that 18.46 g (0.04 mol) of 4'-acetyl-4- (p-chlorobenzyloxy) -biphenyl was used instead of 4'-acetyl-4-benzyloxybiphenyl. Reaction, work-up and purification (+)
-4- (p-Chlorobenzyloxy-4 '-(1-hydroxyethyl) biphenyl (V-5) is obtained.

Next, an asymmetric hydrolysis reaction, a post-treatment and purification were carried out according to Example 3, except that propionic acid chloride was used instead of octanoic acid chloride, to give (+)-4- (p-chlorobenzyloxy-4). There was obtained a propionate of '-(1-hydroxyethyl) biphenyl. ▲ [α] ²⁵ _D ▼
+ 44 ° (c = 1, CHCl ₃ ) Examples 8 to 10 Reaction was carried out under the same conditions as in Example 1 except that the same molar number of the acid chloride shown in Table 1 was used instead of propionic acid chloride (5.5 mmol). , Post-treatment and purification, and the results shown in Table 1 were obtained.

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

▲ [α] ²⁵ _D ▼ + 55 ° (c = 1, CHCl ₃ ) Melting point 125 ° C. Example 12 In place of (+)-4-benzyloxy-4 ′-(1-hydroxyethyl) biphenyl (V-2) (+)-P-
Benzyloxy-1-phenethyl alcohol (V-1)
1.14 g (4 mmol) of (2S, 3S) -2-chloro-3-
2-S-methylbutanoic acid 0.49 instead of methylpentanoic acid
The reaction, work-up and purification are carried out in the same manner as in Example 4 except that g (4.8 mmol) is used.

1.36 g of 2S-methylbutanoic acid ester of (+)-p-benzyloxy-1-phenethyl alcohol (95% yield)
I got

▲ [α] ²⁵ _D ▼ +88 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5326 Example 13 (−)-p-benzyloxy which is an unreacted ester in the asymmetric hydrolysis reaction obtained in Example 1 1-phenethyl alcohol acetate 13.5 g, methanol 100 ml and
The reaction is carried out at 20 ° C. for 5 hours with 30 g of 10% NaOH. After the completion of the hydrolysis reaction, 50 ml of water and 200 ml of toluene are added for extraction. The toluene layer is washed with water and concentrated under reduced pressure. The residue is purified by silica gel column chromatography.

11.1 g of (-)-p-benzyloxy-1-phenethyl alcohol (V-6) are obtained.

Next, 1.14 g (5 mmol) of (V-6) 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. After completion of the acylation reaction, post-treatment and purification were carried out according to Example 1, and 1.57 g of hexanoic acid ester of (-)-p-benzyloxy-1-phenethyl alcohol was obtained (yield 96.5%). I got

▲ [α] ²⁵ _D ▼ -67 ゜ (c = 1, CHCl ₃ ) ▲ n ²⁵ _D ▼ 1.5281

Claims (5)

(57) [Claims] 1. The compound of the general formula (I) (Wherein, R represents an alkyl group which may contain a halogen atom having 1 to 20 carbon atoms, A represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms or an alkoxyl group, and n represents 1 Or 2, and an asterisk indicates an asymmetric carbon.) An optically active benzene derivative represented by the formula: 2. A compound of the general formula (II) (Wherein, A, n and * represent the same meaning as described above) and an optically active alcohol represented by the general formula (III) R-COOH (III) (wherein, R represents the same meaning as described above) The method for producing an optically active benzene derivative represented by the general formula (I), characterized by reacting with an aliphatic carboxylic acid or a derivative thereof represented by the following formula: 3. A compound of the general formula (IV) (Wherein, R ′ represents a lower alkyl group, and A and n have the same meanings as described above.) Wherein one of the optically active forms of the esters is preferentially hydrolyzed. Asymmetric hydrolysis using an esterase having the ability to decompose gives an optically active alcohol represented by the general formula (II), and then the optically active alcohol and a fat represented by the general formula (III) A method for producing an optically active benzene derivative represented by the general formula (I), characterized by reacting with an aromatic carboxylic acid or a derivative thereof. 4. The formula (V) (Wherein, A and n represent the same meaning as described above), and an ester represented by the general formula (IV) is obtained by reacting an alcohol represented by
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 (II), Then, a method for producing an optically active benzene derivative represented by the general formula (I), wherein the optically active alcohol is reacted with an aliphatic carboxylic acid represented by the general formula (III) or a derivative thereof. 5. A compound of the general formula (VI) (Wherein A and n have the same meanings as described above), to obtain an alcohol represented by the general formula (V), and then the alcohol and a lower alkyl carboxylic acid The ester is reacted to obtain an ester represented by the general formula (IV), 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. Obtaining an optically active alcohol represented by the general formula (II), and then reacting the optically active alcohol with an aliphatic carboxylic acid or a derivative thereof represented by the general formula (III). A method for producing the optically active benzene derivative represented by (I).