JPH04190795A - Production of optically active chroman derivative - Google Patents

Abstract

PURPOSE:To obtain the title derivative, an optically active intermediate of vitamin useful for drugs, foods, cosmetics, etc., by treating a specific compound in an aqueous medium in the presence of an enzyme source having activity of asymmetrically hydrolyzing the compound. CONSTITUTION:A compound shown by formula I (R1 is H, aralkyl, alkanoyl or aroyl; R3 is alkyl or aryl) is hydrolyzed in an aqueous medium in the presence of an enzyme source (e.g. triacylglycerol lipase) having activity of asymmetrically hydrolyzing the compound to give the objective compound shown by formula II (R'1 is R1; R2 is H, alkanoyl or aroyl).

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a method for producing chroman derivatives, which are optically active intermediates of vitamin E, used in pharmaceuticals, foods, cosmetics, and the like.

Conventional techniques A known method for synthesizing optically active or romantic derivatives is to chemically resolve the corresponding carboxylic acid using an optically active amine, and then esterify and reduce this [Journal of Organic Chemistry (Jou
RNA of Organic Chemistry
).

vol, 41.3505 (1976), Helvetica Chimic
Acta), vol 61.837 (1978)
].

The purpose of the present invention is to provide a method for producing Roman derivatives, which are important as intermediates for the synthesis of optically active forms of vitamin E used in pharmaceuticals, foods, cosmetics, etc.

According to the present invention, means for solving the problem are represented by the formula (II) (wherein R1 represents hydrogen, an aralkyl group, an alkanoyl group, or an aroyl group, and R3 represents an alkyl group or an aryl group). A compound is treated in an aqueous medium in the presence of a source of enzyme having the activity of asymmetrically hydrolyzing the compound, and the compound is treated with the formula (1) (wherein, R'1 is the same as R1, R2 is hydrogen, A method for producing an optically active form of a chroman derivative represented by formula (1), which is characterized by collecting an optically active form of a chroman derivative represented by formula (1) and formula (III) (representing an alkanoyl group or an aroyl group). , R1 has the same meaning as above) and the compound represented by the formula (IV> R, C0OH(TV) (wherein, R4 represents an alkyl group or an aryl group).

) or a reactive derivative thereof in an organic solvent in the presence of an enzyme source having an activity to asymmetrically unnucleate the compound represented by formula (I [I), It is possible to provide a method for producing an optically active chroman derivative, which comprises collecting an optically active chroman derivative represented by the formula (wherein R'1 and R3 have the same meanings as above).

In the formula, the alkyl group and the alkyl moiety of the alkanoyl group in the definition of each group include linear alkyl having 1 to 7 carbon atoms, such as methyl, ethyl, propyl, methyl, pentyl, hekynyl, heptyl, and the like. Examples of the aryl group and the aryl moiety of the aroyl group include pheninopenaphthyl. Examples of the aralkyl group include benzyl and phenethyl.

The enzyme source used in the above-mentioned hydrolysis reaction and unarylation reaction has the activity of asymmetrically hydrolyzing the compound represented by the formula (n) [hereinafter referred to as compound (old)] or the enzyme source of the formula (I
Any enzyme, whether purified or crude, can be used as long as it has the activity of asymmetrically acylating the compound represented by I[) [hereinafter referred to as compound (III)] or its containing substance.

As an enzyme, trianruglycerol lipase (EC
03,1,1,3, also known as lipase), lipoprotein lipase (EC,3,1,1,34), and carboxyesterase (EC,3,1,1,1).

These enzymes are produced by microorganisms and animal tissues, and are already commercially available and can be easily obtained.

A specific example of a commercially available enzyme is lipoprotein lipase (
Lipase P-Amano (derived from Pseudomonas genus; manufactured by Amano Pharmaceuticals), Polysympancreatic lipase (derived from pig pancreas; manufactured by Sigma), Lipase (derived from Candida genus; manufactured by Sigma) , Big River Esterase (derived from pig liver; manufactured by Sigma), Neurase F Amano (derived from Rhizopus, manufactured by Amano Pharmaceutical), Lipase AP-4 Amano (derived from Aspergillus; manufactured by Amano Pharmaceutical), Lipase MA
Examples include P-10 (derived from the genus Mucor; manufactured by Amano Pharmaceutical Co., Ltd.), immobilized enzyme Lipozyme (derived from the genus Mucor; manufactured by Novo), and immobilized enzyme 5P382 (derived from the genus Candida; manufactured by Novo).

Enzyme contents include microbial cells, culture fluids, or the like of microorganisms that have the ability to produce enzymes that have the activity of asymmetrically hydrolyzing compound (II) or the activity of asymmetrically unnucleating compound (I). Processed products include:

Examples of microorganisms that have the ability to produce such enzymes include Pseudomonas spp.
, Candida, Mucor (Aspergillus),
Rhizopus, Bacillus, Ba
cillus), Arthrobacter (Arthr.
obacter), Pichia, Chromobacterium ([: chromobacter iu
Microorganisms belonging to the genus Humicola and Peninrium (Pen+c+ll+um) can be mentioned.

Examples of the bacterial cell-treated product include dried bacterial cells, surfactant and/or organic solvent additives, lytic enzyme-treated products, immobilized bacterial cells, and enzyme preparations extracted from the bacterial cells.

Examples of the processed culture solution include culture solution concentrates, dried products, surfactants and/or organic solvent additives, and lytic enzyme-treated products.

Asymmetric hydrolysis of compound (II) is carried out by mixing the enzyme source and compound (n) in an aqueous medium and stirring or shaking the mixture.

As the aqueous medium, water or a mixture of water and ethanol, dimethylformamide, acetone, etc. can be used.

The asymmetric hydrolysis reaction is carried out at a temperature of 10 to 70°C, preferably 2
It is carried out at a temperature of 0-50°C and a pH of 5-8.

Neutralizes the organic carboxylic acid produced by hydrolysis and p
In order to keep H constant, it is preferable to use a buffer, and buffers of inorganic salts such as sodium phosphate and potassium phosphate, and buffers of organic salts such as sodium acetate and sodium citrate can be used.

Moreover, a base such as sodium hydroxide or potassium hydroxide can be used in combination.

Compound (II), which is a substrate, is added at a concentration of 01 to 5 to the reaction solution.
0% by weight, preferably 0.5-25% by weight! used in %,
The enzymes are used in an amount of 0.1 to 50% by weight based on the weight of the substrate. At this time, in order to disperse the substrate compound (II) well in the reaction solution, an anionic surfactant such as Nonion (manufactured by NOF Meji Co., Ltd.), Span (manufactured by Kanto Kagaku Co., Ltd.),
A surfactant such as ,)su)n

Although the reaction varies depending on the reaction temperature, substrate concentration, fermentation s1, etc., the reaction is usually completed in 1 hour to 6 days.

In this reaction, when R1 has an acyl group such as an alkanoyl group or an aroyl group, the acyl group may also undergo hydrolysis at the same time depending on the type of enzyme source or reaction conditions.

Asymmetric acylation of compound (I[[)
is dissolved in an organic solvent, a carboxylic acid represented by formula (IV) or a reactive derivative thereof, and the enzyme source are added, followed by stirring or shaking.

As the organic solvent, aromatic solvents such as toluene and benzene, ether solvents such as diethyl ether and isopropyl ether, and solvents such as chloroform are used alone or in combination.

Specific examples of the carboxylic acid represented by formula (TV) include lower aliphatic carboxylic acids such as acetic acid, propionic acid, and butyric acid;
Examples include aromatic carboxylic acids such as benzoic acid. Examples of its reactive derivatives include its acid anhydrides and esters such as methyl, ethyl, vinyl, and isopropenyl.

Compound (II[), which is a substrate, was added at a concentration of 0.5 to the reaction solution.
The carboxylic acid represented by the formula <IV) and its reactive derivatives are used in an amount of 1 to 5 equivalents relative to compound (III), and the enzymes are used in an amount of 0 to 20% by weight relative to the weight of the substrate. It is used in an amount of 1 to 80% by weight.

The reaction is carried out at a temperature of -20 to 50°C, usually for 1 hour to
It will be completed in 7 days. In addition, when R1 is hydrogen in this reaction, the hydroquine group may also be acylated at the same time depending on the type of enzyme source or reaction conditions.

In either reaction, the optically active form of compound (1) can be obtained by separating and collecting the product and unreacted material from the reaction mixture. Isolation and purification can be carried out by filtering off enzymes, followed by washing, solvent extraction, vacuum concentration, silica gel column chromatography, etc.

The optically active Roman derivative thus obtained is useful as a synthetic intermediate for vitamin E.

For example, the optically active 6-benzyloxy-2-(2'-benzoyloxyethyl)- obtained in Example 1 described below
2,5,7,8-tetramethylchroman was converted to 6-pendyloquine-2-(2'-formylmethyl)-2,5,7,8-tetramethylchroman by the method of Reference Example 6, and then converted to Helvetica Chem. Force Actor (Helveti)
ca Chimica Acta, Vol, 59
゜FaSc, 1 (1976) -Nr, 33-34
Vitamin E can be produced according to the method described in [Page 290].

Examples and reference examples are shown below.

The optical purity of the compounds in the Examples was analyzed by high performance liquid chromatography (HPLC) using a column holding an optically active carrier.

HPLC column: CHIRALCEL 00 (manufactured by Daicel Chemical Co., Ltd.) 4.6 x 250 mm Detection: UV 254 nm Mobile phase, hexane: ethanol: diethylamine = 9
00 + 100: Q, ram temperature; room temperature flow rate; 0.4 mf/min Example 1 6-benzyloxy-2-(2'-benzoyloxyethyl)-2,5,7,8-tetramethyl Hydrolysis of 6-benzyloxy-2-(2'-benzoyloxyethyl)-2,5,7 by Chroman's lipoprotein lipase
, 2.5 g of 8-tetramethylchroman was dissolved in 6-dimethylformamide, and Triton X was added as a surfactant.
-100 (manufactured by Hanui Chemical Co., Ltd.) 0.1M containing 0.5%
Add 300ml of potassium phosphate buffer (pH 7.0),
Furthermore, 125 mg of lipoprotein lipase was added.

While keeping the reaction temperature at 30°C and pH at 7.0,
Allowed time to react. Salt was added to the reaction solution to saturate it, insoluble matter was filtered through Celite, and the filtrate was extracted three times with ethyl acetate.

The ethyl acetate layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield 0.95 g of a low polar oil and 1.
1g was obtained. The low polar oily substance showed the following physical properties and was identified as optically active 6-benzyloxy-2-('2'-benzoyloxyethyl)-2,5,7,8-tetramethylchroman (yield 39 %).

'H-N M R (CDCl2) δppm 1.
30 (3H, s), 2.13 (3H, s), 2.2
H3H,s), 2.24(3H,s), 1.8-2
．． 2 (4H, m), 2.68 (2H, t, J=
8Hz), 4.56 (2H, dt.

J=4Hz, J=8Hz), 5.75(2)1
．． s), 7.3-8.3 (IOH, m) IRV
,,, (cm-') 2930(s), 17
20(s), 1695(m).

1605 (m), 1585 (m), 1500 (
m), 1455(s), 1415(s),
1380(s), 1320(s), 12
75(s), 1255(s).

1215 (m), 1180 (o+), 1160
(+rI), 1115(s), 1095(s)
, 740(m), 715(sC700(s>optical purity 91%e, e, [cx], =2.26(
CHCf3. Cm1.2) In addition, the highly polar oily substance exhibits the following physical properties and is optically active 6-penzylokine-2-(
The product was identified as 2'-hydroquinethyl)-2,5,7,8-tetramethylchroman (yield 60%).

') I-NMR (['De13) δppm 1.
28 (3H, s), 2.03 (3H, s), 2.1
6(3B, s), 2.2H3H, s), 1.6-
2.2 (4H, 1Tl), 2.64 (2H, t, J
=8)1z), 3.90(2H,t.

J=6Hz), 4.68(2H,s), 7.2-7
．． 6(5H,m)IRνwax (Cm-') 34
30(S), 2930(S), 1500(m).

1460(s), 1415(s), 1375(s)
, 1255(s), 1170(s), 109(1
(s), 106(1(s), 1020(s), 9
20 (m).

755(m), 740(s), 700(s) Optical purity 57%e,e,Ca: ], --8,11(CH
I': β3+ Cm1.15) Example 2 Hydrolysis of 6-pendyloquine-2-(2'-benzoyloxyethyl)-2,5,7,8-tetramethylchroman by dry bacterial cells 6-pendyloquine-, -2-(2'-benzoyloxyethyl)-2,5,7,8-tetramethylchroman 25
mg was dissolved in 504 dimethylformamide, and 0.0 mg containing 0.5% Triton χ-100 as a surfactant was prepared.
, 2wd2 of 1M potassium phosphate buffer (pH 7,0) was added, and Bacillus sp.
haericus) I FO3341 dried bacterial cells 2
5 mg was added. The mixture was shaken at 30°C and reacted for 5 days.

After adding salt to the reaction solution and making it saturated, it was extracted three times with ethyl acetate and analyzed by HPLC. As a result, 6-benzyloxy-
2-(2'-benzoyloxyethyl)-2,5,7,
8-tetramethylchroman, yield 84%, optical purity 1
3% e, e, and also 6-penzylokine-2-
(2'-Hydroquinethyl l-2,5゜7.8-tetramethylchroman, yield*16%, optical purity 66%e,e
Generated with.

Examples 3 to 5 Hydrolysis of 6-benzyloxy-2-(2'-acyloxyethyl)-2,5,7,8-tetramethylchroman 6-benzyloxy-2-(2'-acyloxyethyl) -2,5,7,8-tetramethylchroman 100mg
was dissolved in 0.25-dimethylformamide and 10 m
1! 0.1M potassium phosphate buffer (p) 17.0)
was added, and further 5 mg of lipoprotein lipase was added. The reaction was carried out at 30°C and analyzed by HPLC.

The results are shown in the table below.

Example 3 [6-benzyloxy-2-(2'-pentanoyloxyethyl)-2,5,7,8-tetramethylchroman hydrolyzate; 6-benzyloxy-2-(2'-hydroxy ethyl)-2,5,7,8-tetramethylchroman Example 4゜Substrate; 6-penzyloquine-2-(2'-hexanoyloquinethyl)-2,5,7,8-tetramethylchroman hydrolyzate ; 6-pendyloquine-2-(2'-hydroxyethyl) -2,5,7,8-tetramethylchroman Example 5゜Substrate; 6-pendyloquine-2-(2'-octanoyloxyethyl) -2,5, 7,8-te)ramethylchroman hydrolyzate; 6-pendyloquine-2-(2'-hydroquinethyl)-2,5,7,8-tetramethylchroman 11 Reaction time: 3 hours: 8 hours 1 Example 6゜6-pendyloquin-2-(2'-acetoquinethyl 1
Hydrolysis of 2,5,7.8-tetramethylchroman (6-benzyloxy/-2-(2'-ace)+dimethyl)
0.1 M potassium phosphate buffer (p)I containing 0.5% Triton Add 2 ml of
5μ of riboprotein lipase was added. The reaction was carried out at 5°C for 16 hours. After the reaction solution was saturated with sodium chloride, it was extracted three times with ethyl acetate and analyzed by HPLC.
7.8-Tetramethylchroman was produced in a yield of 73% and an optical purity of 28%; −
Tetramethylchroman has a yield of 27% and an optical purity of 52%.
e, e, was generated.

Example 7 Lopenzyloxy-2-(2'-acetoquinethyl)
-Hydrolysis of 2,5,7,8-tetramethylchroman (
Alternative method) 6-benzyloxy-2-(2'-acetoquinethyl i
2,5.7.8-tetramethylchroman 20mg and dimethylformamide 50ρ added and dissolved, 0.1M potassium phosphate buffer (p)l containing 0.5% Triton X-100 as a surfactant 7.0 ), and Bacillus thuringiensis (Bacillus thuringiensis).
Add 20 mg of dried bacterial cells of S. ingiensis and
The reaction was carried out at 0°C for 5 hours. The reaction solution was saturated with sodium chloride, extracted three times with ethyl acetate, and analyzed by HPLC.
6-benzyloxy-2-(2'-acetoquinethyl)
-2,5,7,8-tetramethylchroman with a yield of 45
%, optical purity 37% e,
7,8-Tetramethylchroman was produced in 55% yield and optical purity of 30%e,e.

Example 8 6-pendyloquin-2-(2'-acetoquinethyl)
-Hydrolysis of 2,5,7,8-tetramethylchroman (
Alternative method) Bacillus thuringiensis
ur+ngiens+s) was cultured at 30° C. for 24 hours in a culture solution containing 1% peptone, 07% meat extract, 0.3% salt, 05% yeast extract, and dehydrated ionized water (pH 7.2). To 2d of this culture solution, 20mg of 6-benzyloxy-2-(2'-acetoxyethyl)-2,5,7,8-tetramethylchroman was dissolved in 50ρ of dimethylformamide, and 3% Triton X~100 was added. 2,504 ml of the water contained in the mixture was added, the well-turbid liquid was added, and the reaction was carried out at 30°C. After the reaction solution was saturated with sodium chloride, it was extracted three times with ethyl acetate and analyzed by HPLC. was produced with a yield of 63% and an optical purity of 22%ee. In addition, 6-penzyloquine-2-(2'-hydroquinethyl)-2,5,7,8-tetramethylchroman was obtained in a yield of 3
7% and optical purity of 45%.

Example 9 Arylation of 6-benzyloquine 7-2-(2'-):)'loquinethyl)-2,5,7,8-tetramethylchroman 6-penzyloquine-2-(2'-hydroquinethyl) )
300 mg of -2,5,7,8-tetramethylchroman was dissolved in a mixture of 3 mf of tetrahydrofuran and 18-m of toluene, 450 mg of benzoic anhydride and 50 μl of lipoprotein lipase were added, and the mixture was stirred at room temperature for 42 hours. The enzyme was filtered out from the reaction solution, washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 170 mg of a low polar oil and 163 cm of a highly polar oil.

The low polar oil has properties other than the specific rotation that match the compound obtained as the low polar oil in Example 1, and is 6-benzyloxy-2-(2'-benzoyl quinethyl)-
It was identified as 2,5,7,8-tetramethylchroman (yield 43%). In addition, the highly polar oily substance has the same physical properties as the compound obtained as the highly polar oily substance in Example 1 other than the specific optical rotation, and has 6-benzyloxy-1(2'-hydroquinethyl)-2,5 ,7,8-tetramethylchroman (yield 54%). As a result of HPL'C analysis, the optical purity was 79% e, e.

Furthermore, the 6-benzyloxy-2-(2
'-Hydroxyethyl)-2,5,7,8-tetramethylchroman (79% e, e,) 163 µm was dissolved in a mixture of 1.5 ml of tetrahydrofuran and 9 rnl of toluene, and 230 µm of anhydrous benzoin was dissolved. Acid and 25 mg of lipoprotein lipase were added, and the mixture was stirred at room temperature for 98 hours. The enzyme was filtered out from the reaction solution, washed with saturated aqueous sodium bicarbonate and saturated brine, dried with anhydrous magnesium sulfate/rum, and concentrated under reduced pressure. The residue was subjected to phosphor gel column chromatography to obtain 9411 g of a low polar oily substance and 88 mg of a highly polar oily substance. The highly polar oily substance has the same physical properties as the compound obtained as the highly polar oily substance in Example 1 other than the specific optical rotation, and has 5-
Benzyloxy-2-(2'-hydroquinethyl)-2
, 5,7,8-tetramethylchroman (yield: 54%). As a result of HPLC analysis, the optical purity was 96%e.
It was e.

Example 10゜5-benzyloxy-2-(2'-hydroquinethyl)
-Unarylation of 2,5,7,8-tetramethylchroman (
Alternative method) 6-benzyloxy-2-(2'-hydroquinethyl)
-2,5,7,8-tetramethylchroman 50mg 0
．． 5- was dissolved in a mixture of tetrahydrofuran and 3 ml of toluene, 90 ml of benzoic anhydride and 15 mg of riboprotein lipase were added, and the mixture was stirred at room temperature for 1 hour. The enzyme was filtered from the reaction solution, washed with saturated sodium bicarbonate solution and saturated saline,
The mixture was dried with anhydrous magnesium sulfate/rum and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 43 cm of a low polar oil and 15 cm of a highly polar oil.

The highly polar oily substance has the same physical properties as the compound obtained as the highly polar oily substance in Example 1 other than the specific rotation, and has 6-benzyloxy-2-(2'- and droxyethyl)-2,5
,7,8-tetramethylchroman (yield: 31
%). As a result of HPLC analysis, the optical purity was 98%e.
It was e.

Reference example 1゜6-hydroxy-2-(2'-hydroquinethyl)-2
, 5,7,8-tetramethylchroman 10 g of trimethylhydroquinone was suspended in 100 d of toluene and 5 g of anhydrous zinc chloride was added. This was heated to 100°C and 17.6 g of 3-methyl-1,3,5-pentanetriol dissolved in 80-dioxane was added.
Furthermore, 10 d of 6N hydrochloric acid was added, and the mixture was heated at 100° C. for 6 hours. After the reaction, the reaction solution was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. Combine the ethyl acetate layers, add water,
It was washed successively with saturated sodium bicarbonate solution and saturated saline solution. After drying over anhydrous magnesium sulfate/lamb, it was filtered and concentrated under reduced pressure, and the residue was purified by nori gel ram chromatography to obtain 7.8 g of a crystalline substance. This substance shows the following physical properties, 6-hydroquine-2-(2'-hydroquinethyl)-
It was identified as 2,5,7,8-tetramethylchroman (yield 47%).

'H-N M R (CDCl2) δI) pm 1
．． 28 (3H, s), 1.6-2.2 (4H, m)
, 2.08 (3H, s), 2.10 (3tl, s
), 2.15 (3H, s), 2.62 (2H, t,
J=8Hz), 3.90(21(,t.

J=6Hz), 4.43(IH, bs)IRν, ,
(cm-”) 3350(s>, 3]50(s)
, 2945(s).

1460(s), 1440(s), 1385(
s), 1260(s), 1120(s), 10
90(s), 1060(s>, 1020(s) Reference example 2゜6-hydroxy-2-(2'~acetoquinethyl)-2
, 5,7,8-Tetramethylchroman production 6-hydroxy7-2-(2'-hydroquinethyl)-2,5,7,
8-Tetramethylchroman Ig was dissolved in 9d(7) tetrahydrofuran, and 50 mj' of hexane was added, followed by 1 ml of acetic anhydride. Immobilized fermentation in this reaction solution! Add 5P-382190■ and leave at room temperature for 2 hours.
The reaction was carried out with stirring for several minutes. After the reaction was completed, the enzyme was filtered off and washed successively with saturated sodium bicarbonate solution and saturated saline. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography to obtain 1.
1 g of oil was obtained. This substance showed the following physical properties and was identified as 6-hydroxy-2-(2'-acetoquinethyl)-2,5,7,8-tetramethylchroman (yield 92%).

') l-NMR (CD[:]3) 699m 1.
10 (3H, s), 1.7-2.2 (4H, m),
2.0-2.3(12)1), 2.66(2H,t,
J=8Hz).

4,0 (IH, bs), 4.04-4.50 (
2)1. m) Reference example 3゜6-benzyloxy-2-(2'-acetoxyethyl)
-Production of 2,5,7,8-tetramethylchroman 6-hydroquine-2-(2'-acetoquinethyl)-2,5,
9.24 g of 7,8-tetramethylchroman was dissolved in 200 g of a 1:1 mixed solvent of dimethylformamide and dimethyl sulfoxide, and while cooling with ice, 7rn1 of benzyl bromide was added, and then dissolved in powder form. hydroxide) I
2.3 g of Jium was added. The mixture was stirred at rVJ for 1 hour and 30 minutes under ice cooling. The mixture was neutralized with 2N hydrochloric acid 30- and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.

The residue was purified by licage gel column chromatography to obtain 10.4 g of an oily substance. This substance exhibits the following physical properties and has the following physical properties:
-acetoxyethyl)-2,5,7,8-tetramethylchroman (yield: 486%).

+1(-NMR(CDC13) 699m 1
．． 32(3t(,s), 2.08(3H,s), 2
．． 12 (3H, s), 2.20 (3M, S), 2
．． 24 (3H, s), 1.6-2.2 (4, m)
, 2.66(28,t, J=8)1z), 4.1
-4.5(2)1. m), 4.74(2)1. s
), 7.3-7.7 (5H, m) Reference example 4゜6-benzyloxy-2-(2'-hydroxyethyl)
-Production of 2,5,7,8-tetramethylchroman 6-benzyloxy/-2-(2'-acetoxyethyl)-2,
5,7,8-tetramethylchroman 5g methanol 5g
0-, 8 ml of 5N sodium hydroxide was gradually added dropwise at room temperature, and the mixture was reacted for 3 hours with stirring. After reaction 2
The reaction solution was neutralized with N hydrochloric acid, concentrated under reduced pressure, a small amount of water was added, and extraction was performed three times with ethyl acetate. The ethyl acetate layer is
The mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by licage gel column chromatography, and the result was 4.3
g of oil was obtained. This substance showed the following physical properties and was identified as 6-benzyloxy-2-<2'-hydroquinethyl)-2,5,7,8-tetramethylchroman (yield 97%).

'H-NMR ((:DC13) 699m 1.2
8 (3H, s), 2.03 (3H, s), 2.16
(3H, s), 2.21 (3H, s), 1.6-2
．． 2 (4H, m), 2.64<28. t, J=8
)1z), 3.90(2)1. t.

J=6Hz), 4.68(2H,s), 7.2-7
．． 6(5H,I'l+)IRV□X(am-') 3
430(S), 2930<s), 1500(m).

1460(s), 1415(s), 1375(s)
, 1255(s), 1170(s), 1090
(s), 1060(s), 1020(s),
920 (m).

755 (m), 740 (S), 700 (s)
) Reference example 5゜6-benzyloxy-2-(2'-benzoyloxy/)
-Production of 2,5,7,8-tetramethylchroman 6-pendyloquine-2-(2'-hydroquinethyl)-2,
3.7 g of 5,7,8-tetramethylchroman was dissolved in birinone 25-, and 2 ml of benzoyl chloride was added dropwise under ice cooling. The mixture was stirred for 6 hours while gradually raising the temperature to room temperature. The reaction mixture was poured into saturated sodium bicarbonate solution, and diluted with ethyl acetate for 3 hours.
Extracted twice. The ethyl acetate layers were combined and washed three times with 4N hydrochloric acid, in the order of saturated copper sulfate aqueous solution, water, and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.9 g of an oily substance.

This substance shows the following physical properties and has the following physical properties: 6-benzyloxy-2
It was identified as -(2'-benzoyloxy)-2,5,7,8-tetramethylchroman. Yield quantitative.

'H-N M R (CDCI δIII] rn 1
．． 39 (3H, s), 2.13 (3H, s), 2.
21 (3H, S), 2.24 (3H, s), 1.8
-2.2 (4H, m), 2.68 (2H, t, J=
8Hz), 4.56 (2H.

dt, J=4Hz, J=8Hz), 5.75(2
8,s), 7.3-8.3(IOH,m) IR! /,,, (cm-') 2930(s),
1720(s), 1695(m).

1605 (m), 1585 (m), 1500 (m)
, 1455(s), 1415(s), 1380(
s), 1320(s), 1275(s), 125
5(s).

1215 (m), 1180 (m), 1160 (m)
, 1115(s), 1095(s), 740(m
), 715(s), 700(s) Reference example 6゜6-benzyloxy-1(2'-formylmethyl)-
Synthesis of 2,5,7,8-Tetramethylchroman Dichloromethane 2-, which had been dried with molecular tubes, was cooled to -78°C under an argon gas atmosphere, 754 drops of oxalyl chloride were added, and dimethyl sulfoquine was further added. 1204 was added dropwise.

After stirring for 2 minutes at -78°C, 200 m
g was dried with a molecular bath, dissolved in dichloromethane, and added dropwise.

After stirring for 30 minutes at -78°C, 0.5% of triethylamine was added.
ml was added, the temperature was gradually raised to room temperature, and the mixture was stirred at room temperature for 30 minutes. Pour the reaction solution into water and dilute with ethyl acetate.
Extraction was performed twice. The ethyl acetate layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.

The residue was purified by licage gel column chromatography to obtain 175 mg of an oily substance. This product shows the following physical properties and is optically active 6-benzyloxy-2-(2
'-formylmethyl)-2,5,7°8-tetramethylchroman.

'H-NMR (CDCl2) 6119m 1.4
0 (3H,s), 1.9 (2H.

t, J=8Hz), 2.08(3)1. s),
2.16 (3H, s), 2.20 (3) 1. s),
2.64 (2H, d, J・3Hz), 2.59 (
2H,t.

J=81(z), 4.70(2H,s), 7.3-
7.8 (5H, m), 9.94 (IH, t, J=3
Hz) IRνsam (cm-') 2950(s), 2
880(s), 2750(m).

1730(s), 1505(s), 1470(
s), 1460(s), 1420(s),
1380(s), 1260(s), 1120(
s), 1100(s).

1070(s), 1025(s), 930(m
), 875(m), 760(s).

740(s), 700(s) [α]"・+8.48 (CHCβ,, C=1.06
) Cα] Pa =926 (CHCf13. [=1
．． 81) Effects of the Invention According to the present invention, it is possible to efficiently provide a taloman derivative, which is an optically active intermediate of vitamin E used in pharmaceuticals, foods, cosmetics, etc.

Claims (2)

[Claims] (1) Formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R_1 represents hydrogen, an aralkyl group, an alkanoyl group, or an aroyl group, and R_3 represents an alkyl group or an aryl group. ) in the presence of an enzyme source having the activity of asymmetrically hydrolyzing the compound,
Processed in an aqueous medium, the formula (I) ▲Mathematical formula, chemical formula, table, etc.▼(I) (In the formula, R'_1 has the same meaning as R_1. R_2 represents hydrogen, an alkanoyl group or an aroyl group. ) A method for producing an optically active form of a chroman derivative represented by formula (I), which comprises collecting an optically active form of a chroman derivative represented by formula (I). (2) Formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) (In the formula, R_1 has the same meaning as above.) and the compound represented by the formula (IV) R_4COOH(IV) (In the formula, R_4 represents an alkyl group or an aryl group) or a reactive derivative thereof in an organic solvent in the presence of an enzyme source having the activity of asymmetrically acylating the compound represented by formula (III). Processing, formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R'_1 and R_2 have the same meanings as above.)
A method for producing an optically active form of a chroman derivative represented by formula (I), which comprises collecting an optically active form of a chroman derivative represented by formula (I).