JPH07300470A - Method for production dl-tocopherol compounds and intermediate for producing the same - Google Patents

Abstract

PURPOSE:To easily obtain a dl-tocopherol compound in a good yield in a short process from an inexpensively available raw material by subjecting the specific compound to a reducing reaction. CONSTITUTION:A compound of formula I [one of the bonds in the group of formula II is a single bond, and the other is a double bond; R<1>R<3> are H, (substituted)hydrocarbon group; X is (protected)hydroxyl group; Y is-CH2-CH2-,- CH=CH-] is subjected e.g. to a catalytic hydrogen addition reaction in the presence of a contact catalyst such as Pd/C in a solvent such as an alcohol compound preferably at approximately 10-60C under a hydrogen pressure of approximately 1-3atm for about 1-2hr to obtain a dl-tocopherol compound of formula III. The compound includes 6-acetoxy-2,5,7,8-tetramethyl-2-(4',8', 12'- trimethyltridecyl) chromane of formula IV.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a process for producing dl-tocopherols and an intermediate for the production. The dl-tocopherols provided by the present invention are useful compounds used in food additives, feed and pharmaceuticals.

[0002]

2. Description of the Related Art Conventionally, dl-tocopherols, especially dl-
It is known that α-tocopherol is synthesized by reacting isophytol with trimethylhydroquinone, for example, as shown in the following scheme.

[0003]

[Chemical 17]

Isophytol used as a starting material in this reaction is known to be synthesized according to the following scheme.

[0005]

[Chemical 18]

[0006]

Isophytol, which is an important raw material for the synthesis of dl-tocopherols, is a multistep process from 6,10-dimethylundec-2-one (C ₁₃ -ketone) in the above method. It requires a lot of steps to be synthesized and the yield is not good. An object of the present invention is to provide a method for producing dl-tocopherols easily and in good yield in a short process from industrial raw materials that are easily available at low cost.

[0007]

Means for Solving the Problems The inventors of the present invention have conducted extensive studies in order to achieve the above-mentioned object, and as a result, produced dl-tocopherols from a raw material which is available at a low cost easily in a short process with a high yield. As a result of discovering a method and further studying, the present invention has been completed.

That is, the present invention is based on the formula (1) (III):

[0009]

[Chemical 19] R ¹ , R ² and R ³ are each a hydrogen atom or a hydrocarbon group which may have a substituent, X is a hydroxyl group which may be protected, and Y is —CH ₂ —CH ₂ — or —CH. = C
A compound represented by H-) is subjected to a reduction reaction of formula (V):

[0010]

[Chemical 20]

(In the formula, R ¹ , R ² and R ³ are each a hydrogen atom or a hydrocarbon group which may have a substituent,
X represents a hydroxyl group which may be protected), (2) carbonization in a hydrocarbon group which may have a substituent represented by R ¹ , R ² or R ^3. The method according to (1) above, wherein the hydrogen group is a hydrocarbon group having 1 to 20 carbon atoms, and (3) R ¹ , R ² and R ³ each may have a hydrogen atom or a substituent. The production method according to (1) above, which is an alkyl group, an alkenyl group, an alkynyl group, an aryl group or an aralkyl group,

(4) The production method according to the above (1), wherein R ¹ , R ² and R ³ are each a methyl group, (5) X is a hydroxyl group, or C _1-6 alkyl, C _6-12 aryl, C _7-20 aralkyl, formyl, C _1-6 alkyl-carbonyl, C
A hydroxyl group protected by _6-12 aryl-carbonyl, C _7-20 aralkyl-carbonyl, silyl ether type protecting group, cyclic acetal type protecting group, alkoxyalkyl or C _6-12 aryloxy-carbonyl (1) above.
(6) X is a C _1-6 alkyl-carbonyloxy group, (7) The production method according to (1) above, wherein X is an acetoxy group, (8) ) The production method according to (1) above, wherein the reduction reaction is a catalytic hydrogenation reaction, (9) formula (II):

[0013]

[Chemical 21] And a compound represented by formula (VI):

[0014]

[Chemical formula 22]

(In the formula, R ¹ , R ² and R ³ are each a hydrogen atom or a hydrocarbon group which may have a substituent,
X represents a hydroxyl group which may be protected), and the compound of formula (III ′):

[0016]

[Chemical formula 23] Other symbols have the same meanings as above) and a compound represented by the formula (V) characterized by subjecting the compound to a reduction reaction:

[0017]

[Chemical formula 24]

(Wherein each symbol has the same meaning as above), (10) The production method according to (9), wherein the reduction reaction is a catalytic hydrogenation reaction, and (11) formula ( IV):

[0019]

[Chemical 25] R ¹ , R ² and R ³ each represent a hydrogen atom or a hydrocarbon group which may have a substituent), and the compound represented by the formula (III ″):

[0020]

[Chemical formula 26] X represents a hydroxyl group which may be protected, and other symbols have the same meanings as above), and a compound represented by the formula (V):

[0021]

[Chemical 27]

(Wherein each symbol has the same meaning as above), the method for producing the compound (12), the ring closure reaction is carried out by treating the compound of formula (IV) with a base. (11) The production method, (13) The production method according to the above (11), wherein the reduction reaction is a catalytic hydrogenation reaction, (14) Formula (I):

[0023]

[Chemical 28] A compound represented by the formula (II) characterized by reacting 2-methyl-2-vinyloxirane:

[0024]

[Chemical 29] A method for producing a compound represented by formula (15), formula (III):

[0025]

[Chemical 30] R ¹ , R ² and R ³ are each a hydrogen atom or a hydrocarbon group which may have a substituent, X is a hydroxyl group which may be protected, and Y is —CH ₂ —CH ₂ — or —CH. = C
A compound represented by H-),

(16) The compound described in (15) above, wherein R ¹ , R ² and R ³ are each a hydrogen atom or an alkyl group which may have a substituent, (17) X is a hydroxyl group, or C _{1 -6} alkyl, C _6-12 aryl, C _7-20 aralkyl, formyl, C _1-6 alkyl-carbonyl, C _6-12 aryl-carbonyl, C _7-20 aralkyl-carbonyl,
The compound according to (15) above, which is a silyl ether type protecting group, a cyclic acetal type protecting group, a hydroxyl group protected by alkoxyalkyl or C _6-12 aryloxy-carbonyl, and (18) formula (III ′):

[0027]

[Chemical 31] R ¹ , R ² and R ³ each represent a hydrogen atom or a hydrocarbon group which may have a substituent, and X represents a hydroxyl group which may be protected),

(19) The compound according to the above (18), wherein R ¹ , R ² and R ³ are each a hydrogen atom or an alkyl group which may have a substituent, (20) X is a hydroxyl group, or C _{1 -6} alkyl, C _6-12 aryl, C _7-20 aralkyl, formyl, C _1-6 alkyl-carbonyl, C _6-12 aryl-carbonyl, C _7-20 aralkyl-carbonyl,
The compound according to the above (18), which is a silyl ether type protecting group, a cyclic acetal type protecting group, a hydroxyl group protected by alkoxyalkyl or C _6-12 aryloxy-carbonyl, (21) formula (III ″):

[0029]

[Chemical 32] R ¹ , R ² and R ³ each represent a hydrogen atom or a hydrocarbon group which may have a substituent, and X represents a hydroxyl group which may be protected),

(22) The compound described in the above (21), wherein R ¹ , R ² and R ³ are each a hydrogen atom or an alkyl group which may have a substituent, (23) X is a hydroxyl group, or C _{1 -6} alkyl, C _6-12 aryl, C _7-20 aralkyl, formyl, C _1-6 alkyl-carbonyl, C _6-12 aryl-carbonyl, C _7-20 aralkyl-carbonyl,
The compound according to (21) above, which is a silyl ether type protecting group, a cyclic acetal type protecting group, a hydroxyl group protected by alkoxyalkyl or C _6-12 aryloxy-carbonyl, and (24) formula (IV):

[0031]

[Chemical 33] R ¹ , R ² and R ³ each represent a hydrogen atom or a hydrocarbon group which may have a substituent),

(25) The compound according to the above (24), wherein R ¹ , R ² and R ³ are each a hydrogen atom or an alkyl group which may have a substituent, and (26) the formula (I
I):

[0033]

[Chemical 34] And a compound represented by:

The hydrocarbon group of the hydrocarbon group which may have a substituent represented by R ¹ , R ² or R ³ in the above formula is a hydrocarbon group having 1 to 20 carbon atoms, for example, an alkyl group. , Alkenyl groups, alkynyl groups, aryl groups, aralkyl groups and the like. Examples of the alkyl group in the above hydrocarbon group include a linear or branched alkyl group having 1 to 20 carbon atoms, and preferably a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, propyl, isopropyl, butyl, sec-
Butyl, tert-butyl, pentyl, hexyl and the like can be mentioned. More preferably, it is a linear or branched alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, etc.). Of these, a methyl group is particularly preferable.

Examples of the alkenyl group in the above hydrocarbon group include an alkenyl group having 2 to 20 carbon atoms, preferably an alkenyl group having 2 to 6 carbon atoms. Specific examples are vinyl, allyl, 2-butenyl, methylallyl, 3
-Butenyl, 2-pentenyl, 4-pentenyl, 5-hexenyl and the like can be mentioned.

Examples of the alkynyl group in the above hydrocarbon group include an alkynyl group having 2 to 20 carbon atoms, preferably an alkynyl group having 2 to 6 carbon atoms. Specific examples include ethynyl, propargyl, 2-butyn-1-yl,
3-butyn-2-yl, 1-pentyn-3-yl, 3-
Pentin-1-yl, 4-pentyn-2-yl, 3-hexyn-1-yl and the like can be mentioned.

Examples of the aryl group in the above hydrocarbon group include an aryl group having 6 to 20 carbon atoms, preferably an aryl group having 6 to 14 carbon atoms. Specific examples include phenyl, 1-naphthyl, 2-naphthyl, biphenylyl, anthryl and the like.

Examples of the aralkyl group in the above hydrocarbon group include an aralkyl group having 7 to 20 carbon atoms, preferably an aralkyl group having 7 to 19 carbon atoms. Specific examples include benzyl, phenethyl, benzhydryl, trityl and the like.

When the above hydrocarbon group has a substituent, examples of the substituent include an alkoxy group, an acyloxy group, an alkoxycarbonyl group, a cyano group and an oxo group. These may further have 1 to 3 appropriate substituents (eg halogen, amino group, etc.). Examples of the alkoxy group include C _1-4 alkoxy groups such as methoxy, ethoxy, propoxy, butoxy and the like. Examples of the acyloxy group include C _1-10 alkylcarbonyloxy groups such as acetoxy, propionyloxy and butyryloxy, and C _6-10 arylcarbonyloxy groups such as benzoyloxy and naphthoyloxy. Examples of the alkoxycarbonyl group include C _1-5 alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like. When the hydrocarbon group has a substituent, the number of substituents is 1 to 3.
Individuals are preferred.

The optionally protected hydroxyl group represented by X includes a hydroxyl group and a hydroxyl group protected by a protecting group. As the protective group when the hydroxyl group is protected,
A protecting group known per se is used. Examples of such a hydroxyl-protecting group include a C _1-6 alkyl group (eg, methyl, tert-butyl etc.), a C _6-12 aryl group (eg, phenyl, naphthyl, biphenylyl etc.), C _7-20 Aralkyl group (eg, trityl, phenylethyl, benzyl etc.), formyl group, C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl etc.), C _6-12 aryl-carbonyl group (eg, benzoyl, naphthylcarbonyl etc.) ), A C _7-20 aralkyl-carbonyl group (eg, phenylacetyl, phenylpropionyl, etc.), a silyl ether type protecting group (eg,
Trimethylsilyl, tert-butyldimethylsilyl, tert
-Butyldiphenylsilyl, etc.), cyclic acetal type protecting groups (eg, tetrahydropyran-2-yl etc.), alkoxyalkyl groups (eg, 2-methoxyethoxymethyl, methoxymethyl etc.), C _6-12 aryloxy-carbonyl groups (Eg, p-nitrophenoxycarbonyl etc.) and the like.

The above formulas (II), (III), (III ') and (I
II '') and (IV),

[0042]

[Chemical 35]

One of the two bonds of (1) represents a double bond and the other represents a single bond. The compounds represented by these formulas are isomers (cis or trans form and position of double bond)
Including a mixture of.

Preferred specific examples of the production method of the present invention will be described below. First, a compound (II) [that is, a compound represented by the formula (II); hereinafter, compounds represented by other formulas may be abbreviated similarly] is reacted with a compound (VI) to produce a compound ( III '). The amount of the compound (II) used is about 0.9 to 1.5 equivalents, preferably about 1 to 1.2 equivalents, relative to the compound (VI). The above reaction is preferably carried out in the presence of a catalyst. Examples of the catalyst include acids such as Lewis acids such as zinc chloride, boron trifluoride, aluminum chloride and stannous chloride; organic acids such as formic acid, acetic acid, p-toluenesulfonic acid and benzenesulfonic acid; inorganic acids such as sulfuric acid. Acid etc. are mentioned. Of these, Lewis acids are preferred.
The amount of the catalyst used is about 0.5 to 2 with respect to compound (VI).
It is equivalent, preferably about 0.7 to 1 equivalent. Also, the above reaction is preferably carried out in a suitable solvent. As the solvent, hydrocarbons (eg, toluene, n-hexane, cyclohexane, benzene, xylene, decalin, etc.), ketones (eg, methyl ethyl ketone, etc.), ethers (eg, ether, dioxane, tetrahydrofuran, etc.), esters Examples thereof include ethyl acetate, ethyl formate, etc., carboxylic acids such as acetic acid, formic acid, etc. Of these, ketones are preferable. These solvents may be used alone or in combination of two or more. Reaction temperature is room temperature ~
The temperature is about 180 ° C, preferably about 60 ° C to 120 ° C. The reaction time is about 0.5 to 18 hours, preferably about 2 to 6 hours. In this reaction, compound (IV) is usually also a by-product in addition to compound (III ′). These can be purified by a conventional method (eg, vacuum distillation, chromatography, etc.) and used in the next step, if desired. This compound (III ')
Alternatively, the compound (IV) is a novel compound having an anti-inflammatory effect, an anti-allergic effect, etc., and is also useful as an anti-inflammatory agent, anti-allergic agent, antihypertensive agent, myocardial metabolism improving agent and the like.

Next, the by-produced compound (IV) is subjected to a ring-closing reaction to obtain the compound (III ″). Further, a mixture of the compound (III ′) and the compound (IV) may be similarly subjected to a ring closure reaction. In this case, the compound (II
A mixture of I ') and compound (III'') is obtained. The ring-closing reaction can be carried out according to a method known per se (eg, Helvetica Chimica Acta)
46 , 2517 (1963)). For example, it can be carried out by treating the compound (IV) or a mixture of the compound (III ′) and the compound (IV) with a base. Examples of the base include aromatic tertiary amines such as pyridine, lutidine, collidine, and dimethylaniline. Of these, pyridine is preferred. The amount of base used is
It is about 10-50 equivalents, preferably about 20-30 equivalents, relative to compound (IV). This reaction may or may not use a solvent. As the solvent, the above-mentioned hydrocarbons, ethers, sulfoxides, amides and the like are used.
Hydrocarbons, sulfoxides or amides are preferably used. The reaction temperature is about 100 to 200 ° C, preferably about 100 to 120 ° C. Reaction time is about 4 ~
It is 30 hours, preferably about 15 to 25 hours.

Simultaneously with or after the ring-closing reaction,
The hydroxyl group may be protected by a method known per se. For example, compound (III ') or (III''), that is, compound (II
When protecting the hydroxyl group of I) with an acyl group, a method of acylating OH can be mentioned. As the acylating agent used in this reaction, an organic carboxylic acid or its reactive derivative is used. As the reactive derivative of the carboxylic acid, for example, an acid halide, an acid anhydride, an active amide, an active ester, an active thioester or the like which can be produced according to a conventional method is used. A concrete description of such a reactive derivative is as follows. 1) Acid halide: For example, acid chloride, acid bromide or the like is used. 2) Acid anhydride: a mixture of symmetrical acid anhydride, mono-C _1-6 alkyl carbonic acid mixed anhydride, and aliphatic carboxylic acid (eg, acetic acid, pivalic acid, valeric acid, isovaleric acid, trichloroacetic acid, etc.) An acid anhydride, a mixed acid anhydride composed of an aromatic carboxylic acid (eg, benzoic acid, etc.) and the like are used. Examples of symmetrical acid anhydrides include C _1-6 alkylcarboxylic acid anhydrides such as acetic anhydride, propionic anhydride and butanoic anhydride. 3) Active amides: eg pyrazole, imidazole, 4
An amide with a substituted imidazole, dimethylpyrazole, benzotriazole or the like is used. 4) Active ester: eg methoxymethyl ester, 1
-Hydroxybenzotriazole ester, N-hydroxy-5-norbornene-2,3-dicarboximide ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester,
In addition to esters such as propargyl ester and pentachlorophenyl ester, esters with 1-hydroxy-1H-2-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide and the like are used. 5) Active thioesters such as 2-pyridylthiol,
A thioester or the like with a heterocyclic thiol such as 2-benzothiazolylthiol is used.

The various reactive derivatives as described above are appropriately selected depending on the kind of carboxylic acid. As the acylating agent, a reactive derivative of sulfonic acid capable of introducing an acyl sulfonate, for example, an acid halide such as methanesulfonyl chloride, benzylsulfonyl chloride, p-toluenesulfonyl chloride, anhydrous methanesulfonic acid, anhydrous p
-Symmetrical acid anhydrides such as toluene sulfonic acid may be used. The amount of the acylating agent such as carboxylic acid, its reactive derivative or sulfonic acid reactive derivative is about 1 to 10 equivalents, preferably about 1 to 4 equivalents, relative to the starting compound (III).

A base is used in this acylation reaction. Examples of the base include tertiary amines [eg, aliphatic tertiary amines such as triethylamine, pyridine, α-, β- or γ
-Picoline, 2,6-lutidine, 4-dimethylaminopyridine, 4- (1-pyrrolidinyl) pyridine, dimethylaniline, aromatic tertiary amines such as diethylaniline, etc.], organic acid salts (eg, sodium acetate), etc. Is used. The amount of the base used is usually about 1 to the starting compound.
It is 100 equivalents, preferably about 1-5 equivalents. This reaction is carried out in a solvent that does not inhibit the reaction or in the absence of a solvent. Examples of the solvent that does not inhibit the reaction include ketones such as acetone; ethers such as diethyl ether, isopropyl ether, tetrahydrofuran, dioxane; carboxylic acids such as acetic acid and propionic acid; nitriles such as acetonitrile; benzene, toluene, xylene, etc. Hydrocarbons; dichloromethane, chloroform, 1,2
-Halogenated hydrocarbons such as dichloroethane; esters such as ethyl acetate; amides such as dimethylformamide, dimethylacetamide; triethylamine, tributylamine, N-methylmorpholine, N-methylpiperidine, N, N-dimethylaniline, etc. Tertiary amines; pyridines such as pyridine, picoline, lutidine and collidine are used. These may be used alone or as a mixture of two or more kinds at an appropriate ratio. The reaction temperature is not particularly limited, but is usually about -30 to 100 ° C, preferably about 1
0 to 50 ° C. The reaction time is about several minutes to several tens hours (for example, about 5 minutes to 30 hours).

For example, when protecting a hydroxyl group with an acetyl group, it is carried out by reacting an acetic acid derivative (eg, acetic anhydride, acetyl chloride, etc.) in a base (eg, pyridine, triethylamine, etc.). The amount of the acetic acid derivative used is about 1-10 equivalents, preferably about 2-5, relative to compound (III).
It is equivalent. Further, for example, when protecting a hydroxyl group with a methoxyethoxymethyl group, it is carried out by reacting with methoxyethoxymethyl chloride in the presence of a base (eg, triethylamine etc.). The amount of methoxyethoxymethyl chloride used is about 1 to 5 equivalents relative to compound (III),
It is preferably about 1.2 to 2 equivalents. As the solvent, the above ethers, hydrocarbons, halogenated hydrocarbons, amides and the like are preferable. The obtained compound (III) is used as a reaction solution or as a crude product, or by a method known per se (eg,
After purification by concentration, extraction, chromatography, distillation, etc.), it can be used in the next step. The obtained compound (III) is a novel compound having an antioxidant action,
It is also useful as an antioxidant in foods, feeds, pharmaceuticals, etc.

Next, the compound (III) obtained by the above reaction
Is subjected to a reduction reaction to obtain the desired compound (V). The reduction reaction can be carried out by a method known per se, for example, a catalytic hydrogenation reaction. It is carried out by introducing hydrogen in the presence of a catalytic catalyst in a suitable solvent. Examples of the solvent used include alcohols (eg, methanol,
Examples thereof include ethanol, isopropanol, etc.), carboxylic acids (eg, acetic acid, etc.), hydrocarbons (eg, hexane, cyclohexane, benzene, toluene, xylene, etc.), and ethers (eg, tetrahydrofuran, dioxane, isopropyl ether, etc.). Of these, alcohols are preferable. You may use these solvent individually or in mixture of 2 or more types. Examples of the catalytic catalyst used include platinum (eg, platinum oxide, hexachloroplatinum (IV) acid, etc.), palladium, rhodium, ruthenium, nickel (eg, Raney nickel, etc.), and a copper-chromium catalyst. Of these, palladium is preferred. If desired, these catalysts may be used in the form of being adsorbed on a carrier. Examples of such a carrier include activated carbon, alumina,
Examples thereof include barium sulfate, calcium carbonate, strontium carbonate and the like. The amount of the catalyst used is about 0.001 to 0.1 equivalent, preferably about 0.015 to 0.020 equivalent, relative to compound (III ′) or (III ″). The reaction temperature is about 10 to 100 ° C, preferably about 10 to 60 ° C. The reaction time is about 0.5 to 5 hours, preferably about 1 to 2 hours. The hydrogen pressure is about 1-10 atmospheres, preferably about 1-3 atmospheres.

The resulting compound (V) can be deprotected with a hydroxyl-protecting group by a method known per se. For example, the hydroxyl group is an alkyl group, an aryl group, an aralkyl group,
When protected with an acyl group, silyl ether type protecting group, cyclic acetal type protecting group, etc., in an aqueous solution or in an alcoholic (eg, methanol, ethanol, etc.) aqueous solution, alkali (eg, sodium hydroxide, potassium hydroxide, etc.) ) Or an acid (eg, hydrochloric acid, sulfuric acid, etc.) for deprotection. Further, for example, when the hydroxyl group is protected by a methoxyethoxymethyl group, it can be deprotected by treating with anhydrous zinc bromide in a halogenated hydrocarbon (eg, methylene chloride, etc.). The desired compound (V) obtained by the production method of the present invention can be isolated and purified by a means known per se, for example, filtration, concentration, solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography, vacuum distillation. Etc., it can be isolated and purified. For example,
After filtering the reaction solution, the filtrate can be concentrated and purified by subjecting it to chromatography. The obtained compound (V) has, for example, an antioxidant action and can be used in a method known per se, for example, for food additives, feed, pharmaceuticals and the like.

The compound (II) used as a starting material in the production method of the present invention has, for example, the formula (I):

[0053]

[Chemical 36]

It can be produced by reacting the compound represented by and 2-methyl-2-vinyloxirane. The amount of 2-methyl-2-vinyloxirane used is about 1 to 3 equivalents, preferably about 1 to 1.2 equivalents, relative to compound (I). The above reaction is carried out in a suitable solvent. Examples of the solvent used include ethers (eg,
Tetrahydrofuran, dioxane, isopropyl ether, etc.), sulfoxides (eg, dimethyl sulfoxide etc.), amides (eg, N, N-dimethylformamide etc.), hydrocarbons (eg, benzene, toluene, xylene etc.) and the like. . These solvents may be used alone or in admixture of two or more. The reaction temperature is about −78 ° to 100 ° C., preferably room temperature to about 70 ° C. The reaction time is about 1 to 10 hours, preferably about 1 to 4 hours. Compound (I) can be produced according to a method known per se. The obtained compound (II) may be used as a reaction solution or as a crude product, or if desired by a method known per se (eg, solvent extraction, concentration, chromatography, distillation, etc.).
Can be used as a starting material for the production method of the present invention after separation and purification by.

[0055]

EXAMPLES The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. Unless otherwise specified,% means% by weight. Example 1

[0056]

[Chemical 37]

0.2 g of 60% sodium hydride (in oil) was suspended in 4 ml of isopropyl ether, and 3,7,11-trimethyl obtained according to the method described in JP-B-38-26657 under a stream of N _2. A solution of 1 g of a mixture (compound (I)) of 3--3-dodecen-1-yne and 7,11-dimethyl-3-methylene-dodec-1-yne (4 g) in isopropyl ether was added dropwise to tetrahydrofuran (THF) 2 m.
l, 1 ml of dimethylsulfoxide (DMSO) was added, and then a solution of 0.42 g of 2-methyl-2-vinyloxirane in 2 ml of isopropyl ether was added dropwise. did. The reaction solution was cooled, saturated brine was added, the layers were separated, and the aqueous layer was further extracted with isopropyl ether. The isopropyl ether layer was dried over sodium sulfate and then concentrated to obtain a crude product. This was subjected to silica gel column chromatography (n-hexane:
Ethyl acetate = 10: 1 v / v) and purified 3,7,11,15-tetramethyl-1,7-hexadecadiene-5-yn-3
580 mg of -ol (compound (II)) was obtained (510 mg of unreacted compound (I) was recovered). The structure was confirmed by NMR. NMR (CDCl ₃ ) TMS δ: 0.90 (s, 3H), 0.97
(s, 3H), 1.10 to 2.40 (m, 16H), 1.43 (s, 3
H), 2.60 (m, 2H), 5.10-5.50 (m, 3H), 5.9
0 to 6.30 (m, H). Example 2

[0058]

[Chemical 38]

Trimethylhydroquinone 0.87 g, toluene 2 ml, methyl ethyl ketone 0.5 ml, acetic acid 0.03 m
l, a mixture of 0.6 g of anhydrous zinc chloride (ZnCl ₂ ) at 100 ° C.
The mixture was heated to 0 ° C., a 1 ml solution of the compound (II) (2 g) in toluene was added dropwise (about 20 minutes), and the mixture was stirred for 5 hours as it was. The reaction solution was cooled, extracted with toluene, washed with water, dried over sodium sulfate and then concentrated to obtain a crude product. This was separated and purified by silica gel column chromatography to obtain 2,5,7,8
-Tetramethyl-2- (4 ', 8', 12'-trimethyl-
4'-tridecene-2'-yne) -6-chromanol (compound (III'a)) (0.77 g) and 3,5,6-trimethyl-
2- (3 ', 7', 11 ', 15'-tetramethyl-2', 7'-
Hexadecadiene-5'-yne) -1,4-benzoquinone (Compound (IVa)) (1.57 g) was obtained. These are N
The structure was estimated by MR. Compound (IVa): NMR (CDCl ₃ ) TMS δ: 0.80 (s, 3)
H), 0.90 (s, 6H), 0.90 to 1.70 (m, 14H), 1.
70-1.85 (m, 6H), 2.00 (s, 9H), 2.85-3.
03 (Broad, 2H), 3.10-3.30 (Broad, 2
H), 4.90-5.70 (m, 3H). Compound (III'a): NMR (CDCl ₃ ) TMS δ: 0.80 (s,
3H), 0.90 (s, 6H), 1.20 (s, 3H), 1.95 (s, 6)
H), 2.10 (s, 3H), 1.00 to 3.00 (m, 20H), 4.
20 (s, H), 5.10 to 5.30 (broad, 2H). Example 3

[0060]

[Chemical Formula 39]

Compound (IVa) (1.57 g) was added to 10 ml of pyridine.
The mixture was dissolved in the mixture, refluxed in nitrogen gas for 24 hours, added with 4 ml of acetic anhydride and stirred at about 100 ° C. for 3 hours for acetylation.
The reaction solution was concentrated, the residue was extracted with ethyl acetate, washed with water, dried over sodium sulfate, and then the solvent was distilled off to obtain a crude product. This is subjected to silica gel column chromatography (n
-Hexane: ethyl acetate = 99: 1) and purified, 6-acetoxy-2,5,7,8-tetramethyl-2- (4 ', 8',
12'-trimethyl-4'-tridecene-2'-in)-
An oily substance of 2H-chromene (compound (III ″ a) (1.26 g) was obtained. The structure was confirmed by NMR. NMR (CDCl ₃ ) TMS δ: 0.87 (s, 3H), 0.93
(s, 6H), 1.10 to 1.70 (m, 13H), 1.57 (s, 3
H), 1.80 (d, 2H, J = 6Hz), 2.07 (s, 6H), 2.
15 (s, 3H), 2.35 (s, 3H), 2.63 ~ 2.83 (m, 2
H), 5.23 (d, H, J≈6 Hz), 5.80 (d, H, J≈10.
5 Hz), 6.60 (d, H, J≈10.5 Hz). Example 4

[0062]

[Chemical 40]

Compound (III ″ a) (1.2 g) was added to ethanol 70
Dissolve in 5 ml and add 5% palladium on carbon (Pd / C) 0.1
g was added, and the mixture was reduced with hydrogen gas (3.0 kg / cm ² ) at room temperature for 2 hours. The reaction solution was filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (n-hexane: ethyl acetate = 99: 1) to give 6-acetoxy-2,5,7,
8-Tetramethyl-2- (4 ', 8', 12'-trimethyltridecyl) chroman (Compound (Va)) (0.98 g) was obtained. NMR (CDCl ₃ ) TMS δ: 1.80 to 1.87 (Me ×
4), 1.20 (Me), 1.00-1.60 (m, 21H), 1.7
5 (t, 2H, J = 6Hz), 1.95 (s, 3H), 2.00 (s, 3
H), 2.07 (s, 3H), 2.30 (s, 3H), 2.60 (t, 2)
H, J = 6Hz).

[0064]

According to the present invention, a method for producing dl-tocopherols is provided. According to the production method of the present invention, dl-tocopherols can be easily produced in a short process in a high yield from industrial raw materials that can be obtained at low cost. Furthermore, according to the present invention, a novel compound useful as an intermediate in the above production method is provided. Some of these compounds have pharmacological activity and are useful not only as intermediates for such production but also as pharmaceuticals.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07C 43/23 C 7419-4H

Claims (26)

[Claims] 1. Formula (III): R ¹ , R ² and R ³ are each a hydrogen atom or a hydrocarbon group which may have a substituent, X is a hydroxyl group which may be protected, and Y is —CH ₂ —CH ₂ — or —CH. = C
A compound represented by H-) is subjected to a reduction reaction (V): (Wherein R ¹ , R ² and R ³ are each a hydrogen atom or a hydrocarbon group which may have a substituent, and X is a hydroxyl group which may be protected). Law. 2. The hydrocarbon group in the optionally substituted hydrocarbon group represented by R ¹ , R ² or R ³ is a hydrocarbon group having 1 to 20 carbon atoms. Manufacturing method. 3. R ¹ , R ² and R ³ are each a hydrogen atom or an alkyl group, an alkenyl group, an alkynyl group, an aryl group or an aralkyl group which may have a substituent. Manufacturing method. 4. The production method according to claim ¹ , wherein R ¹ , R ² and R ³ are each a methyl group. 5. X is a hydroxyl group, or C _1-6 alkyl, C
_6-12 aryl, C _7-20 aralkyl, formyl, C _1-6 alkyl-carbonyl, C _6-12 aryl-carbonyl, C
_{The process according to} claim 1, wherein the hydroxyl group is protected with _7-20 aralkyl-carbonyl, a silyl ether type protecting group, a cyclic acetal type protecting group, an alkoxyalkyl or a C _6-12 aryloxy-carbonyl. 6. The method according to claim 1, wherein X is a C _1-6 alkyl-carbonyloxy group. 7. The production method according to claim 1, wherein X is an acetoxy group. 8. The method according to claim 1, wherein the reduction reaction is a catalytic hydrogenation reaction. 9. Formula (II): embedded image And a compound represented by the formula (VI): (Wherein R ¹ , R ² and R ³ each represent a hydrogen atom or a hydrocarbon group which may have a substituent, and X represents a hydroxyl group which may be protected). Formula (III ') obtained by the reaction: Other symbols have the same meanings as above) and are subjected to a reduction reaction of formula (V): (Wherein each symbol has the same meaning as described above). 10. The production method according to claim 9, wherein the reduction reaction is a catalytic hydrogenation reaction. 11. Formula (IV): embedded image R ¹ , R ² and R ³ each represent a hydrogen atom or a hydrocarbon group which may have a substituent) and are subjected to a ring closure reaction to obtain a compound of formula (III ″): Chemical 8] X represents a hydroxyl group which may be protected, and other symbols have the same meanings as above), and a compound represented by the formula (V): (Wherein each symbol has the same meaning as described above). 12. The method according to claim 11, wherein the ring-closing reaction is carried out by treating the compound represented by the formula (IV) with a base. 13. The production method according to claim 11, wherein the reduction reaction is a catalytic hydrogenation reaction. 14. Formula (I): embedded image A compound represented by the formula (II) characterized by reacting a compound represented by the formula with 2-methyl-2-vinyloxirane: The manufacturing method of the compound represented by. 15. Formula (III): R ¹ , R ² and R ³ are each a hydrogen atom or a hydrocarbon group which may have a substituent, X is a hydroxyl group which may be protected, and Y is —CH ₂ —CH ₂ — or —CH. = C
H-indicating). 16. The compound according to claim 15, wherein R ¹ , R ² and R ³ are each a hydrogen atom or an alkyl group which may have a substituent. 17. X is a hydroxyl group or C _1-6 alkyl,
C _6-12 aryl, C _7-20 aralkyl, formyl, C _1-6
Alkyl-carbonyl, C _6-12 aryl-carbonyl,
The compound according to claim 15, which is a hydroxyl group protected by C _7-20 aralkyl-carbonyl, a silyl ether type protecting group, a cyclic acetal type protecting group, an alkoxyalkyl or a C _6-12 aryloxy-carbonyl. 18. Formula (III ′): embedded image R ¹ , R ² and R ³ each represent a hydrogen atom or a hydrocarbon group which may have a substituent, and X represents a hydroxyl group which may be protected). 19. The compound according to claim 18, wherein R ¹ , R ² and R ³ are each a hydrogen atom or an alkyl group which may have a substituent. 20. X is a hydroxyl group, or C _1-6 alkyl,
C _6-12 aryl, C _7-20 aralkyl, formyl, C _1-6
Alkyl-carbonyl, C _6-12 aryl-carbonyl,
_19. The compound according to claim 18, which is a hydroxyl group protected by C _7-20 aralkyl-carbonyl, a silyl ether type protecting group, a cyclic acetal type protecting group, an alkoxyalkyl or a C _6-12 aryloxy-carbonyl. 21. Formula (III ″): embedded image R ¹ , R ² and R ³ each represent a hydrogen atom or a hydrocarbon group which may have a substituent, and X represents a hydroxyl group which may be protected). 22. The compound according to claim 21, wherein R ¹ , R ² and R ³ are each a hydrogen atom or an alkyl group which may have a substituent. 23. X is a hydroxyl group, or C _1-6 alkyl,
C _6-12 aryl, C _7-20 aralkyl, formyl, C _1-6
Alkyl-carbonyl, C _6-12 aryl-carbonyl,
The compound according to claim 21, which is a hydroxyl group protected by C _7-20 aralkyl-carbonyl, a silyl ether type protecting group, a cyclic acetal type protecting group, an alkoxyalkyl or a C _6-12 aryloxy-carbonyl. 24. Formula (IV): embedded image R ¹ , R ² and R ³ each represent a hydrogen atom or a hydrocarbon group which may have a substituent). 25. The compound according to claim 24, wherein each of R ¹ , R ² and R ³ is a hydrogen atom or an alkyl group which may have a substituent. 26. Formula (II): embedded image The compound represented by.