JPH01226852A - Production of optically active benzene derivative - Google Patents

Abstract

NEW MATERIAL:An optically active benzene derivative shown by formula I (R is 1-20C alkyl or alkoxyalkyl; A is H, lower alkyl, lower alkoxy or halogen; n is 1 or 2; * is asymmetric carbon). EXAMPLE:(+)-4-(1-S-2'-Methylbutoxyethyl)benzoic acid. USE:Useful as an intermediate for agricultural chemicals, drugs, etc. and also suitable as an intermediate for liquid crystal compounds. PREPARATION:An optical active ether derivative shown by formula II (A is H, lower alkyl, lower alkoxy or halogen) is debenzylated to give a compound shown by formula I. The debenzylation reaction is usually carried out by catalytically hydrogenating with hydrogen in the presence of a hydrogenating catalyst or hydrolysis. The amount of the catalyst used is preferably 0.05-0.3pt.wt. based on 1pt.wt. compound shown by formula II. The reaction is carried out preferably at 10 deg.C-60 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a compound of the general formula (I) (wherein R represents an alkyl group having 1 to 20 carbon atoms or an alkoxy alkyl group; n is 1 or 2, and the * mark indicates an asymmetric carbon).

<Prior Art> The optically active benzene derivative represented by the general formula (1) is useful as an organic electronic material, and is also used as an intermediate for medicines, agricultural chemicals, etc.; Nothing is known about optically active benzene derivatives, and of course nothing is known about their production methods.

<Problems to be Solved by the Invention> The optically active benzene derivative represented by the above general formula (summer) is useful as an organic electronic material as described above, but is particularly important as an intermediate for liquid crystal compounds, for example: As shown in Figure 3, it is possible to lead to a liquid crystal compound by reacting it with phenols, and this compound has very excellent properties as a ferroelectric liquid crystal.

Means for Solving the Problems> The present invention provides a method for producing such a new and useful optically active benzene derivative represented by the general formula (), wherein the optically active benzene derivative is the general formula (
It) (In the formula, A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, or a halogen atom, and R%n and the square mark have the same meanings as above.) The optically active ether derivative represented by the following formula is debenzylated. It can be manufactured by

This debenzylation reaction is usually carried out by catalytic hydrogenation or hydrolysis of the optically active ether derivative (1N) with hydrogen in the presence of a water catalyst.

In the debenzylation reaction by catalytic hydrogenation, 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 such catalyst used is determined by the amount of optically active ether derivative (I
Usually 0. The amount is in the range of 1 to 0.5 times by weight, preferably 0.005 to 0.8 times by weight.

The reaction is usually carried out in a solvent, such as water,
Aliphatic hydrocarbons such as dioxane, tetrahydrofuran, methanol, ethanol, n-propyl alcohol, acetone, dimethylformamide, toluene, dichloromethane, ethyl acetate, aromatic hydrocarbons, alcohols, ethers, ketones, esters, halogenated hydrocarbons, etc. Inert solvents are used alone or in mixtures for the reaction.

This reaction is carried out under normal or increased hydrogen pressure, and the amount of hydrogen absorbed is determined by the optically active ether derivative (ff
) The reaction is preferably terminated when the amount becomes 1 to 1.2 times the amount.

The reaction temperature is -10°C to 100°C, preferably 10°C.
~60°C.

After the reaction is complete, the desired optically active benzene derivative (1) can be obtained by removing the catalyst from the reaction mixture by filtration, etc., and then concentrating it. It can be purified by chromatography or the like.

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

Examples of the alkali used in such hydrolysis include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, and calcium hydroxide;
Examples include alkali metal hydrogen and alkaline earth metal carbonate, and it is preferable to use these as an aqueous solution.

certain It is usually used in the range of 1 to 10.

Although the reaction is carried out in the presence of a surplus of water, an organic solvent (preferably a water-soluble organic solvent such as methanol, ethanol, tetrahydrofuran, etc.) may be present if necessary.

The reaction temperature is usually in the range of -20°C to 100°C,
There is no particular restriction on the reaction time.

After the reaction is completed, the organic solvent is removed from the reaction mixture as necessary, the reaction solution is precipitated with acid, and the desired optically active benzene derivative (I) is extracted and concentrated. Can you get it?

An optically active nityl derivative (seedling), which is a raw material in this reaction, has the general formula ((2) (wherein A%n and the bottle mark have the same meanings as above).

) Optically active alcohols represented by the general formula (5) (wherein R has the same meaning as above, and X represents a halogen atom or 10302R', where R' is a lower alkyl group or a substituted It can be produced by reacting with an alkylating agent shown below.

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

The alkylating agent (5) used in this reaction refers to halides such as chlorides, bromides, and iodine, or sulfuric esters ( methanesulfonic acid ester, ethanesulfonic acid ester, benzenesulfonic acid ester, toluenesulfonic acid ester, etc.).

Methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, isopropyl, isobutyl, 2-methylbutyl, 2- Methylhexyl, isopentyl, 2-
Methyloctyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl,
Methoxyhexyl, methoxyhbutyl, methoxyoctyl, methoxynonyl, methoxydecyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, ethoxyhexyl, ethoxyhbutyl, ethoxyoctyl, ethoxynonyl, ethoxydecyl, propoxymethyl, propoxyethyl, propoxypropyl, propoxybutyl, propoxypentyl,
propoxyhexyl, propoxyoctyl, propoxydecyl, butoxyethyl, butoxyethyl, butoxypropyl, butoxybutyl, butoxypentyl, butoxyhexyl, butoxyhebutyl, butoxynonyl, pentyloxymethyl, pentyloxyethyl, pentyloxypropyl, pentyloxybutyl, Pentyloxypentyl, pentyloxyoctyl, pentyloxydecyl, hexyloxymethyl, hexyloxyethyl, hexyloxypropyl, hexyloxybutyl, hexyloxypentyl, hexyloxyhexyl, hexyloxyoctyl, hexyloxynonyl, hexyloxydecyl, heptyloxy Methyl, heptyloxyethyl, heptyloxypropyl, heptyloxypentyl, octyloxymethyl, octyloxyethyl, decyloxymethyl, decyloxyethyl, decyloxypropyl.

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

↓ However, it is usually in the range of 1 to 5 equivalents.

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

The reaction temperature is usually -50°C to 120°C, preferably -80°C.
It is in the range of 0°C to 100°C.

After the reaction is completed, the optically active ether (II) can be obtained in good yield by ordinary separation means such as extraction, separation, concentration, etc., and if necessary, by column chromatography, recrystallization, etc. However, the reaction mixture can be used as it is for the next step.

Optically active alcohols, which are the raw materials for this reaction (
The powder is an ester represented by the general formula (V) (wherein A and n have the same meanings as above, and R' represents a lower alkyl group), among optically active forms of the ester. It can be produced by hydrolyzing one of the optically active forms of the esters (asymmetric deicing) using an esterase that has the ability to hydrolyze either one of the esters.

The esterase-producing microorganism used in this reaction is not particularly limited, and may be any microorganism that produces an esterase capable of asymmetrically hydrolyzing esters (V).

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

Specific examples of such microorganisms include Enterobacter sp., Arthrobacter sp., Brevibacterium sp., Pseudomonas sp., alkaline earth metals, Micrococcus sp., Chromobacterium sp., Microbacterium sp., Corynebacterium sp. , Bacillus, Lactobacillus, Trichoderma, Candida, Satucharomyces, Rhodotonogin, Chrysitococcus, Torulopsis, Pichia, Penicillium, Aspergillus, Rhizopus, Mucor, Aureopacidium, Actinomucor Examples include microorganisms belonging to the genus Nocardia, genus Streptomyces, genus Hansenula, and genus Achromobacter.

The above-mentioned microorganisms are cultured according to a conventional method, and a culture solution can be obtained by, for example, liquid culture.

For example, use a sterilized liquid medium [malt extract/yeast extract medium for frequent use of mold and yeast (1 ml of water to 5 ml of peptone,
Glucose 10? , malt extract 81, yeast extract 8? For bacteria, dissolve glucose 101, peptone 5F, meat extract 51, and NaC1'B S' in 11 parts of water, and use 1) H7,
2)] and cultured with reciprocating shaking at 20 to 40°C for 1 to 8 days, and solid culture may be performed if necessary.

Furthermore, some of these microbial-derived esterases are commercially available and can be easily obtained. Specific examples of commercially available esterases include the following.

Pseudomonas lipase [Lipase P (Amano Pharmaceutical)], Aspergillus lipase [Lipase AP (Amano Pharmaceutical)], Mucor lipase [Lipase M-,
11, P (manufactured by Amano Pharmaceutical Co., Ltd.)], Candida cylindrasse lipase [Lipase MY (manufactured by Octa Sangyo Sangyo)], alkaline earth metal lipase [Lipase PL (manufactured by Octa Sangyo Sangyo Co., Ltd.)]
],] Achromobacter lipase [Lipase AL (Polysaccharide Industry!! Ri), Arthrobacter lipase [Lipase Godo BSL (Godo Sake Refining)], Chromobacterium lipase (Toyo Jozo Co., Ltd.), Rhizopus delemer lipase [Talibase (manufactured by Tanabe Seiyaku)], lipase of the genus Rhizopus [Lipase Saiken (Osaka Bacteria Research Institute)].

Further, animal/plant esterases can also be used, and specific examples of these esterases include the following.

Steapsin, pancreatin, lid liver esterase, Willai Germ x x y lace.

The esterase used in this reaction is an enzyme obtained from animals, plants, or microorganisms, and its usage forms include purified enzyme, crude fermentation, enzyme-containing material, microbial culture solution, culture prey, bacterial cells, cultured They can be used as needed in various forms such as coins and processed products, and enzymes and microorganisms can also be used in combination. Or again,
It can also be used as an immobilized enzyme immobilized on a resin or the like, or as an immobilized bacterial cell.

The asymmetric hydrolysis reaction is usually carried out by vigorously stirring a mixture of the raw material ester (V) and the above-mentioned enzyme or microorganism in a buffer solution.

As the buffer, commonly used buffers of inorganic acid salts such as sodium phosphate and potassium phosphate, buffers of organic acid salts such as sodium acetate and sodium citrate, etc. The pH is preferably 8 to 11 for a culture solution of a microorganism that is not alkaliphilic or an alkaline esterase, and the pH is preferably 5 to 8 for a culture solution of a microorganism that is not alkalophilic or an esterase that does not have alkali resistance. Concentration is usually 0.05-2
M, preferably in the range of 0.05-0.5M.

The reaction temperature is generally 10 to 60''C, and the reaction time is generally 8 to 70 hours, but is not limited thereto.

After completion of such hydrolysis reaction, the hydrolysis reaction solution is extracted with a solvent such as methyl isobutyl ketone, ethyl acetate, ethyl ether, etc., the solvent is distilled off from the organic layer, and the concentrated residue is treated with column chromatography. By the method of Can be separated.

The optically active esters obtained here can be further hydrolyzed as necessary to produce optically active alcohols that are enantiomers of the optically active alcohols obtained previously.

In addition, when a lipase belonging to the genus Pseudomonas or Arthrobacter sp. is used as the lipase in this asymmetric ice-thawing reaction, an optically active alcohol (2) with relatively high optical purity can be obtained.

Additionally, during this hydrolysis, in addition to the buffer, organic solvents inert to the reaction such as toluene, chloroform, methyl isobutyl ketone, dichloromethane, etc. can be used, and by using these, asymmetric ice thawing can be advantageously performed. You can also do it.

Esters M, which are the raw materials for this reaction, are acylated by reacting alcohols represented by the general formula (b) (where A and n have the same meanings as above) with lower alkyl carboxylic acids. It can be equipped by

In this acylation, anhydrides or acid halides of lower alkylcarboxylic acids are used as the lower alkylcarboxylic acids, specifically acetic anhydride, acetic chloride or bromide, propionic anhydride, propionic acid chloride or bromide, butyryl Examples include chloride or bromide, pareyl chloride or bromide.

In this reaction, the amount of the lower alkylcarboxylic acid to be used is required to be at least 1 equivalent to the alcohol (b), and although the upper limit is not particularly limited, it is preferably 4 times the amount by equivalent.

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

When a solvent is used in this reaction, examples of the solvent include aliphatic or Solvents inert to the reaction of aromatic hydrocarbons, ethers, halogenated hydrocarbons, etc. may be used alone or in mixtures, and the amount used is not particularly limited.

Examples of the catalyst include organic or inorganic basic substances such as dimethylaminopyridine, diethylaminopyridine, triethylamine, tri-n-butylamine, pyridine, picoline, imidazole, sodium carbonate, and potassium bicarbonate; Organic or inorganic acids such as sulfonic acid and sulfuric acid can also be used as catalysts.

The amount of catalyst used varies depending on the type of lower alkyl carboxylic acids used, the combination of catalysts used, etc., and is not necessarily specified, but for example, when using an acid halide as the lower alkyl carboxylic acids, it is is 1 equivalent or more.

The reaction temperature is usually -80°C to 100°C, preferably -20°C to 90°C.

The reaction time is not particularly limited, and the raw material alcohol (7)
The end point of the reaction can be defined as the point in time when it disappears from the reaction system.

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

Furthermore, alcohols (b), which are the raw materials for this reaction, can be converted into alcohols by reducing ketones represented by the general formula (■) (wherein A and n have the same meanings as above). It can be produced by reduction using a reducing agent that can be used.

As such a reducing agent, sodium borohydride, lithium borohydride, or borohydride is preferably used, and the amount used is at least 1% based on the raw material ketones (■).
The amount is required to be at least twice the equivalent amount, and is usually in the range of 1 to 10 times the equivalent amount.

This reaction is usually carried out in a solvent, such as
For example, solvents inert to the reaction such as tetrahydrofuran, dioxane, ethyl ether, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, toluene, benzene, chloroform, ethers such as dichloromethane, halogenated hydrocarbons, and alcohols may be used alone or in mixtures. used.

The reaction temperature is usually in the range of -80°C to 100°C.

However, the temperature is preferably in the range of -20"C to 90C.

From the reaction mixture thus obtained, liquid separation, concentration,
Through operations such as distillation and crystallization, alcohols ~ θ can be obtained in good order, but in order to obtain the esters in the next step, it is not necessarily necessary to isolate the alcohol G, and the reaction mixture You may proceed to the next step as is.

Note that ketones (■), which are raw materials for such a reaction, can be produced by thermal spraying by reacting beryl halides and acetyl carboxylic acids in a conventional manner, for example, as shown below.

Effects of the Invention> Thus, according to the method of the present invention, an optically active benzene derivative represented by the general formula (1), which is a novel compound, can be produced with high optical purity and in good yield. It is not only useful as an intermediate for agricultural chemicals and medicines, but also
Very useful as an intermediate for liquid crystal compounds.

Example> The present invention will be explained below with reference to Examples.

Example 1 4-Acetylbenzoic acid benzyl ester 80,4951' (0
, 12 mol), ethanol 50d and chloroform 1
50d was charged, and to this was added 2.85' (0.06 mol) of sodium borohydride at 15-25°C over 10 minutes.

After incubating at the same temperature for 2 hours, the reaction mixture was poured into ice water.
Extract twice with 200.1/20% ethyl acetate. After washing the organic layer with water, it was concentrated under reduced pressure to give 4-(1-hydroxyethyl)benzoic acid benzyl ester (Vl-1) 29
．． 2P (yield 95%) was obtained.

nD 1.5680 Next, the (VI-1) 27.96P (011 mol) obtained here was mixed with 150 yxl of toluene and 5011 ml of pyridine.
Dissolved in a mixture of 1 and 9.4% of acetyl chloride.
25' (0.12 mol) is added over a period of 2 hours at 15-20°C. Insulate at the same temperature for 1 hour and at 30-35°C for 2 hours. After the reaction is completed, the mixture is cooled to 10° C. or below, 800 ml of 8N hydrochloric acid solution is added, and the organic layer is separated and washed sequentially with water, 5% sodium bicarbonate solution, and water. The organic layer was concentrated under reduced pressure and further purified by column chromatography to obtain 4-(
1-acetoxyethyl)benzoic acid benzyl ester (V
-1) 82.145' (yield 98%) was obtained.

The (v-1) 19.08P (64 mmol) obtained above was mixed with 400 t of 0.1 M phosphate buffer (LiH7,0), 10 m of chloroform and Amano Lipase rPJ4F, and incubated at 40-45°C for 20 Stir vigorously for an hour.

After the reaction is complete, the reaction mixture is diluted with 60% methyl isobutyl ketone.
Extract at 0 m. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a mixture of hexane:ethyl acetate = 12:1 as an eluent (→-4-(1-hydroxyethyl)phenylcarboxylic acid benzyl ester (III -1) 7.21PC〔α)” +85.4゜(
C-1, CHCII,), n” 1.5691)
I got it.

Add to this 0.1554 (6 mmol) of sodium hydride.
Add and keep warm at 80-85°C for 1 hour.

Next, 2.11 (6 mmol) of n-dodecyl tosylate is added at 20-25°C, and the mixture is reacted at 40°C for 6 hours. After the reaction is complete, the reaction mixture is poured into water and extracted with 50 ml of ethyl acetate. After washing the organic layer with water,
Concentrate under reduced pressure. The concentrated residue was purified by column chromatography to obtain (→-4-(1-dodecyloxy
'(Yield: 82%).

nD-1,5016 [α)%” + 82.4° (C=1, CHCl),)
Next, (II-1) IP (2.5 mmol, 0.27 mmol of 5% Pd-carbon (50% W6t), 10 kg of methanol and 5 kg of ethyl acetate are mixed and hydrogenated under normal pressure. Hydrogen absorption The reaction is stopped when the amount reaches 60 m/s, the catalyst is removed by furnace, and the furnace liquid is concentrated.The residue is purified by chromatography using toluene-acetic acid (20:1) (→-4-(
1-dodecyloxyethyl)benzoic acid (1-1) 0.7
Obtained 2F.

Melting point 4.9.5~50℃ (α)”5+82.7°(c=1.CHCJ,
) Example 2 (1.2 mmol of 0.5PC of (11-1) obtained in Example 1), 1.51 l of 10% sodium hydroxide aqueous solution and 10111 methanol were mixed and reacted at 25 to 80°C for 5 hours. . After the reaction is complete, adjust the pH to 8 with 1096 hydrochloric acid.
and extracted with toluene 20d. After washing the organic layer with water, it was concentrated under reduced pressure, and the residue was chromatographed using PF.
I to obtain (→-4-(1-dodecyloxyethyl)benzoic acid (1-1) 0175').

Melting point 49.5-50.5°C (α]2.. + 82.6° (C=1, CHCil
,) Example 8 (m-1) 156 P (0,01
mol) in 20 m of N-methylpyrrolidone, and
Cool c1. Add 0.81 P of sodium hydride to this
(0,018 mol) and kept warm at 80-85°C for 1 hour. Next, n-hexyl tosylate 8.6P (0,
014 mol) at 20 to 25°C and reacted at 40″C for 5 hours. After the reaction, the reaction mixture was poured into water and extracted with 50 ml of ethyl acetate. The organic layer was washed with water. After that, it is concentrated under reduced pressure.The concentrated residue is purified by column chromatography to obtain (4)-4-(1-hexyloxyethyl)benzoic acid benzyl ester (n-2)8
．． 115' (yield 92%) was obtained.

(n-2) 1.6954 (5 mmol) obtained above, 5%
Pd-carbon 0.1? and 15 d of ethanol are mixed,
Hydrogenate under normal pressure. The reaction was stopped when the amount of hydrogen absorbed reached 120 g, and the following post-treatment and purification were carried out according to Example 1 to obtain (t)-4-(1-hexyloxyethyl)benzoic acid (1-2) 1. 215' (yield 97.5%) was obtained.

n'', 71.5040 (α〕ru'+65.4° (C=1, CHCf3) Example 4 Obtained in Example 8 (If -2> 0.85 P C2
, 5 mmol), tetrahydrofuran 5 wl and 5
% potassium hydroxide aqueous solution is mixed, the pH is adjusted to 2 with 10% hydrochloric acid water, and tetrahydrofuran is distilled off under reduced pressure. The residue was extracted with 20ml of toluene, the organic layer was washed with water, and purified according to Example 2 (→-4(1-hexyloxyethyl)benzoic acid (1-2) 0,65'
(yield 96%).

n%' 1.5088 [α)%5+64.4° (C=1, CHCf, ) Example 5 In a flask similar to that used in Example 1, 4=acetylbenzoic acid methylbenzyl ester 82,175' (0, 1
2 mol), ethanol 50d1 dichloromethane 100m
1 and 50 m of tetrahydrofuran, and add 1
Sodium borohydride 2.8F (0
, 06 mol) over a period of 10 minutes.

After incubating at the same temperature for 2 hours, the reaction mixture was poured into ice water.
The same post-treatment as in Example 1 was carried out to obtain 4-(1-hydroxyethyl)benzoic acid methylbenzyl ester (Vl-8
) 81.48P (yield 97%) was obtained.

Next, (VI-8) 29.71SL (0,11
200 ml of dichloromethane and 50 ml of pyridine
- acetyl chloride 9.4
50 tons of a dichloromethane solution containing 25i' (0.12 mol) are added dropwise at room temperature. After about 2 hours, the reaction solution was
Pour into 800 ml of N hydrochloric acid and perform extraction operation. The organic layer was washed successively with water, 7% sodium bicarbonate solution, and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 4-(1-acetoxyethyl)benzoic acid methylbenzyl ester (v-8) 88.854 (yield 97%) as a pale yellow oil.

15.65' (50 mmol) of (V-8) obtained above was added to 0
．． 8 M phosphate buffer (pH 7,0) 200 m/1 chloroform 10 t/and Amano lipase rPJ85'
and stir vigorously for 24 hours at 38-40°C.

After the reaction is completed, the reaction mixture is extracted with 600% ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was separated and purified by column chromatography using a mixture of hexane:ethyl acetate = 12:1 as an eluent to obtain methylbenzyl (t)-4-(1-hydroxyethyl)benzoate. Ester (1t-
8) 5.95P C(α)2D,' + 86.8°
(C=1, CH(J'3), 11%51.5688) was obtained.

1.85P (5 mmol) of (i-8) obtained above is dissolved in dimethylformamide 15d and cooled to 10°C.

To this, sodium hydride 0.15 F (6 mmol)
Add and keep warm at 80-85°C for 1 hour. Next, ω−
Add 1.555' (6 mmol) of ethoxypropyl tosylate at 20-25°C and react at 85-40°C for 5 hours. After completion of the reaction, post-treatment according to Example 1,
Purified (t)-4-(1-ω-ethoxypropoxyethyl)benzoic acid methylbenzyl ester (rx-8)
1.87F (yield 77%) was obtained.

Then (n-3) 0.895c (2.6 mmol), 6%
Pd-C0,1? and 10 d of methanol are mixed and subjected to catalytic hydrogenation under normal pressure. The reaction was terminated when the hydrogen absorption amount reached 60 d, and the following post-treatment and purification were carried out according to Example 1 to obtain ((1)-4-(1-ω-ethoxypropoxyethyl)benzoic acid (I-8) 0.615' (yield 97%) was obtained.

nD 1.5077 [α)%, '+59.7° (C=1, CHCl3) Example 6 4-acetylbenzoic acid methoxybenzyl ester instead of 4-acetylbenzoic acid methylbenzyl ester 84.
The reaction and post-treatment were carried out in the same manner as in Example 5 on the same molar scale except that 09P (0.12 mol) was used to obtain the following intermediate.

4-(1-Hydroxyethyl)benzoic acid methoxybenzyl ester (VI-4) Yield 95.5% 4-(1-acetoxyethyl) Benzoic acid methoxybenzyl ester (V-4) Yield 98.5% ( g)-4-(1- and droxyethyl)benzoic acid methoxybenzyl ester 2, 8 4 F (α]%' + 8 7. 2° (C=1, CFiC
l. )nD 1.5721 1.4BP (!It-4) obtained above (5 mmol) is dissolved in dimethylformamide 15s*/ and cooled to 10°C. Add 0.161 (6 mmol) of sodium hydride to this and keep warm at 80-86°C for 1 hour. next,
Methyl iodide2. IP (15 mmol) at 20-2
Add one trowel at 5°C and react at the same temperature for 8 hours and then at 40°C for 8 hours. After the reaction was completed, it was post-treated and purified according to Example 1 to obtain (→-4-(1-methoxyethyl)benzoic acid methoxybenzyl ester (II-4 > 1.
865' (yield 91%) was obtained.

Next, (II-4) 0.7 5F (
2.5 mmol), palladium oxide 0. 0 8 P and 10 sg of methanol are mixed and catalytically hydrogenated under normal pressure. The reaction was terminated when the hydrogen absorption amount reached 68 m, and the following was followed by post-treatment and purification according to Example 1 to obtain (g)-4-
(1-methoxyethyl)benzoic acid (1-4) 0.48P
(yield 96%).

Excitation point 99~100″Crc<),”+9 4. 2° (C=1, CH
CJ, ) Example 7 In a flask similar to that used in Example 1, 4'-acetyl-
4-Biphenylcarboxylic acid benzyl ester 88.1'
(0.1 mol) and tetrahydrofuran 200jI/
and 50 d of ethanol, and heated at 15 to 25°C with 8.0 d of sodium borohydride. 8F (0.1 mol) is added over a period of 10 minutes. After incubating at the same temperature for 2 hours, the reaction solution was poured into ice water and extracted twice with 800 tons of chloroform. After washing the organic layer with water, it was concentrated under reduced pressure to give 4'
-(1-hydroxyethyl)-4-biphenylcarboxylic acid benzyl ester (Vl-5) 8 2.9 F
(yield 99%).

(VI-5) 29.95'(0.09
mol) toluene 150 t/and pyridine 5 mol).

Dissolved in d, this 1-door acetyl chloride 9.42F
(0.12 mol) was added over 2 hours at 15-20"C. Then, it was heated at 40-45°C for 2 hours at the same temperature.
Incubate at C for 2 hours. After the reaction is completed, the mixture is cooled to below 10°C, 800 m/m of 8N hydrochloric acid is added, and the organic layer is separated and washed successively with water, 5% sodium bicarbonate, and water. The organic layer was concentrated under reduced pressure, and the residue was further purified by column chromatography to obtain 4'-(1-acetoxyethyl)-4-biphenylcarboxylic acid benzyl ester/l/(V-5).
88.05' (yield 98%) was obtained.

(V-5) 29.9F (0.08%) obtained here
0. 1M phosphate buffer (pH 7.5) 800H
11 Chloroform 80Wll and Amanolipase rP
Mix with J6F and stir vigorously at 80-86°C for 20 hours. After the reaction is complete, the reaction mixture is extracted with 60 Qt/ml of methyl isobutyl ketone.

The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a chloroform:ethyl acetate (12:1) mixture as an eluent to give (t)-4'-(1-hydroxyethyl)-
4-biphenylcarboxylic acid benzyl ester (11-5
) 10.61 [[α): 1'+28.7° (C= 1.
0, CFiCf13), melting point 104-106°C]
I got it.

(III-5) 1.665' (5 mmol) obtained here
is dissolved in 20 g of dimethylformamide and cooled to 10"C. Add 0.15 F (6 mmol) of sodium hydride to this and keep warm at 80-85 °C for 1 hour. Next, dissolve n-octyl tosylate. 1.7P (6 mmol) is 2
Add at 0-25°C and react at 40°C for 5 hours. After the reaction is completed, the reaction mixture is poured into water and extracted with 50 y of chloroform. After washing the organic layer with water, it is concentrated under reduced pressure. The concentrated residue was purified by column chromatography to obtain (4)-4'-(1-octyloxyethyl)-4-biphenylcarboxylic acid benzyl ester (n-
5) 1.495' (yield 81%) was obtained. [-]V+
(n-5) 1.08P (2.8 mmol) obtained on 26.2° (C=1, CHCl!s), 5% Pd-
0.15' carbon, 15 ffi of tetrahydrofuran and 5 d of methanol are mixed and catalytically hydrogenated under normal pressure.

The reaction is terminated when the amount of hydrogen absorbed reaches 66 d.

After removing the catalyst from door to door and concentrating the P solution, it was purified by chromatography to obtain (+-4'-(octyloxyethyl)-4-biphenylcarboxylic acid (I-5) 0.76? (98% yield)
I got it.

[α)%, 11+67.5° (C=1, CHCJ,) Melting point 189-140°C Example 8 1.665' (5 mmol) of (III-5) obtained in Example 7 was added to 20 m of dimethylformamide. Dissolve, 10°
Cool to C. To this, sodium hydride 0.155'
(6 mmol) and incubate at 80-85°C for 2 hours. Next, propyl bromide 1.22P (10 mmol)
was added at 20 to 250°C, and the reaction was continued at the same temperature for 2 hours and then at 40 to 50°C for 6 hours. After completion of the reaction, post-treatment and purification were carried out according to Example 7 to obtain (2)-4'-(1-propoxyethyl)-4-biphenylcarboxylic acid benzyl ester (II-6) 1,50,% (yield 80 %)
I got it.

(n-6) 1.05F (2.8 mmol) obtained above
, 5% Pd-carbon 0.1! i4. Tetrahydrofuran 1
5m and methanol 51E/ are mixed and hydrogenated under normal pressure. The reaction is stopped when the amount of hydrogen absorbed reaches 68 m. After removing the catalyst by furnace and concentrating the P solution, the residue was purified by chromatography (eluent: chloroform/acetic acid = 10
/1) (-+-) -4'-(1-propoxyethyl)-4-biphenylcarboxylic acid (I-6) 0,77
S' (yield 97.5%) was obtained.

[α]%' + 76.9° (C=1, CHCJ3)
Melting point 172-173°C Example 9 In a flask similar to that used in Example 1, 4'-acetyl-
4-biphenylcarboxylic acid p-chlorobenzyl ester 86.54 (0.1 mol), chloroform 150M! and 50 d of ethanol, and at 15-25°C, 8.8 F (0.1 mol) of sodium borohydride was added over 10 minutes. After incubating at the same temperature for 2 hours, the reaction solution was poured into ice water and extracted twice with 200 ml of Suimu ethyl. After washing the organic layer with water, it was concentrated under reduced pressure to obtain 4'-(1-hydroxyethyl)-4-biphenylcarboxylic acid p-chlorobenzyl ester (VI-7) 86.5F (yield 99
．． 6%).

Obtained here (VI-7) 88. OF (0.09 mol) is dissolved in 150 d of toluene and pyridine 50- and to this is added 9.427 ml (0.12 mol) of acetyl chloride at 15-20° C. over a period of 2 hours. Thereafter, the mixture is kept at the same temperature for 1 hour and at 40 to 50°C for 2 hours. After the reaction is complete, cool to below 10°C and add 3N hydrochloric acid
00d was added, and the organic layer was separated and washed sequentially with water, 5% sodium bicarbonate, and water. The organic layer was concentrated under reduced pressure, and the residue was further purified by column chromatography to obtain 4'-(
1-acetoxyethyl)-4-biphenylcarboxylic acid p
-Chlorbendi kx stell (V-7) 86.4 I
F (yield 99.0%) was obtained.

The obtained (V-7) 82.7F (0.08 mol) was 0
．． Mix with 800 m/m of 1M phosphate buffer (pH 7,5), 30 d of chloroform and Amanolipase [PJ6F and stir vigorously at 40-45 °C for 20 h. After the reaction is completed, the reaction mixture is extracted with 600 d of methyl isobutyl ketone.

The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography using a hexane:ethyl acetate (12:1) mixture as an eluent (→-4'-(1-hydroxyethyl)-4-biphenylcarboxylic acid p -chlorobenzyl ester (II
! -7) 18.851'(shi)%,'-1t7°(e=
0.544, CHcfI3), melting point 108-110.5
°C] and unreacted ester at 16.5F.

The (1-7)8.65P (Lot remole) obtained here was dissolved in 80 t/d of dimethylformamide and cooled to 10°C. Add 0.48P (12 mmol) of sodium hydride to this and keep warm at 80-85°C for 1 hour. Next, 5.154 (12 mmol) of n-octadecyl tosylate is added at 20 to 25°C, and the mixture is reacted at 40°C for 5 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with 50 ml of ethyl acetate.

After washing the organic layer with water, it is concentrated under reduced pressure.

The concentrated residue was purified by column chromatography, and (
+)-4'-<1-octadecyloxyethyl)-
4-biphenylcarboxylic acid p-chlorobenzyl ester (IF-7>5.075' (yield 82%) was obtained.C
(a):' + 21.1° (C==0.98, CH
C73), n%' 1.5814) then obtained here (If-7') 8.15', 5% Pd-carbon 0.
5F, 40ml of tetrahydrofuran, and 10ml of methanol are mixed and hydrogenated under normal pressure. The reaction is terminated when the amount of hydrogen absorbed reaches 120 d. After removing the catalyst from door to door and concentrating the P solution, chloroform/acetic acid (10
/1) to obtain (4)-4'-(1-
Octadecyloxyethyl)-4-biphenylcarboxylic acid (I-7') was obtained.

[, x);' + 518° (C=1, CHCl3)
Melting point 145-146°C Example 10 1.28 de(5 mmol) of (1-1) obtained in Example 1 was dissolved in 15ffi/dimethylformamide and heated at 10°C.
Cool to Next, sodium hydride 0.15 F (6
mmol) and kept at 80-85°C for 1 hour. To this, 5-2-methylbutyl tosylate/, llF 5'
(6'?, Rimol) at 20-25°C,
React at ~50°C for 5 hours. Hereinafter, according to Example 1, it was post-treated and purified (→-4-(1-8-2'-methylbutoxyethyl)benzoic acid benzyl ester (II-8).
) 1.40F (yield 86%) was obtained.

Next (II-8) 0.81? (2.5 mmol), 5%
Using 0.2 F of Pd-carbon (50% wei) and 15 t of methanol, the reaction, post-treatment and purification were carried out in the same manner as in Example 1 (→-4-(1-8-2'-methylbutoxyethyl) Benzoic acid (■-8) 0.58F (yield 98%) was obtained.

n: 31.4718 (b)%,' + 46.8° (C=1, CH
Cl, ) (margin below)

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R is an alkyl group or alkoxyalkyl group having 1 to 20 carbon atoms, A is a hydrogen atom, a lower alkyl group, Represents a lower alkoxyl group or a halogen atom. n is 1 or 2, * indicates an asymmetric carbon.) A general formula characterized by debenzylation of an optically active ether derivative represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R, n, and *marks have the same meanings as above.) A method for producing an optically active benzene derivative represented by the following. (2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, or a halogen atom. n is 1 or 2, and the * mark indicates an asymmetric ) and an optically active alcohol represented by the general formula R-X (wherein R represents an alkyl group or an alkoxyalkyl group having 1 to 20 carbon atoms, and X represents a halogen atom or - Indicates OSO_2R″, where R
'' represents a lower alkyl group or an optionally substituted phenyl group.) The method for producing an optically active benzene derivative according to claim 1, wherein the optically active ether derivative is produced by reacting with an alkylating agent represented by (3) General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, or a halogen atom, and R' represents a lower alkyl group. n is 1 or 2) A claim for producing optically active alcohols by asymmetrically hydrolyzing the esters shown in (2) using an esterase capable of hydrolyzing one of the optically active forms of the esters. Method for producing optically active benzene derivatives as described in Section 2. (4) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, or a halogen atom. The method for producing an optically active benzene derivative according to claim 8, wherein the ester is produced by reacting the alcohol represented by (n is 1 or 2) with a lower alkyl carboxylic acid. (6) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, A represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, or a halogen atom. n is 1 or 2.) 5. The method for producing an optically active benzene derivative according to claim 4.