JP2000273095A - Production of alpha-tocopherol derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To industrially produce a highly pure α-tocopherol derivative without forming hardly removable impurities by condensing trimethylhydroquinone with phytols by using a specific catalyst. SOLUTION: The condensation reaction of (A) trimethylhydroquinone of formula I with (B) an allyl alcohol derivative of formula II (n is 0 or 1-5; L is hydroxy, a halogen, acetoxy, methanesulfonyloxy or the like) or (C) an alkenyl alcohol of formula III is carried out in the presence of (D) zinc iodide to provide (E) the objective α-tocopherol derivative of formula IV. The component D is preferably the one derived from zinc chloride or zinc bromide (preferably zinc chloride), hydrogen halide (preferably hydrogen chloride, hydrogen bromide or hydrogen iodide), and sodium iodide or potassium iodide in the reaction system. The obtained component E is useful as an antisterility vitamin, a blood lipid depressing agent or the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an α-tocopherol derivative (IV) useful as an anti-fertility vitamin, a blood lipid lowering agent, a blood flow enhancer, an active oxygen scavenger, a cell aging inhibitor, an antioxidant and the like. It relates to a manufacturing method.

[0002]

2. Description of the Related Art Conventionally, α-tocopherol derivative (IV) is
Trimethylhydroquinone (I) represented by the following chemical formula,

[0003]

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Any of phytols represented by the following chemical formula

[0005]

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Has been produced by condensation by Friedel-Crafts reaction.

[0007]

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In the Friedel-Crafts reaction, a catalyst is indispensable, and specifically, zinc chloride, aluminum chloride,
Lewis acids such as stannic chloride, ferric chloride, titanium tetrachloride and boron trifluoride / ether complex, or a combination of Lewis acids and protic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and the like have been used. For example, JP-B-45-21835 discloses a method using zinc chloride and hydrogen halide, and JP-A-477-14176 discloses a method using ferric chloride and hydrogen chloride.
No. 1712 discloses a method using stannic chloride and hydrogen chloride,
Japanese Patent Publication No. 47-8821 discloses a method using a boron trifluoride / ether complex and an acid. However, in practice, zinc chloride is frequently used from the viewpoint of raw material availability, yield, product purity, operability, price, and the like.

[0009]

[Problems to be Solved by the Invention] Conventionally, zinc chloride has been frequently used as a Lewis acid catalyst in the production of α-tocopherol derivative (IV) as described above. Zinc chloride is an excellent catalyst in terms of the reaction yield, but has a problem that impurities having the following structure are generated, which cannot be removed by ordinary industrial purification means such as distillation.

[0010]

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Although the above impurities vary depending on the reaction conditions, they are usually produced in the order of 0.4% to several%, and the desired α-
Since it is very close to the tocopherol derivative (IV), its chemical properties such as boiling point and polarity are very similar.
Purification was not possible. Therefore, except for preventing this impurity from being formed as much as possible during the reaction, high purity α-tocopherol derivative (IV), which is required as a raw material for pharmaceuticals, foods, cosmetics, etc., cannot be obtained at present. . As described above, in the conventional method for producing the α-tocopherol derivative (IV) using zinc chloride as a catalyst, there is a problem in the product purity, and an industrially superior catalyst has been desired instead.

[0012]

Accordingly, the present inventors have conducted intensive studies with the aim of improving the above-mentioned problems of the conventional catalyst. As a result, surprisingly, the intended purpose was achieved by using zinc iodide as a catalyst, and extremely high purity α-
The present inventors have found that the tocopherol derivative (IV) can be industrially produced, and have completed the present invention.

Accordingly, an object of the present invention is to provide an anti-fertility vitamin,
Provided is an industrially excellent method for producing a high-purity α-tocopherol derivative (IV) useful as a blood lipid lowering agent, a blood flow enhancer, an active oxygen scavenger, a cell aging inhibitor, an antioxidant, and the like. It is in.

The allyl alcohol derivative (II) according to the present invention is represented by the following general formula.

[0015]

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In the formula, n represents an integer of 0 to 1 and L represents a hydroxyl group, a halogen atom, an acetoxy group, a methanesulfonyloxy group, an ethanesulfonyloxy group, a benzenesulfonyloxy group or a toluenesulfonyloxy group. Specific examples of the halogen atom include a chlorine atom, a bromine atom, an iodine atom, and a fluorine atom.

More specifically, the following compounds can be mentioned, but the allyl alcohol derivative in the present invention
(II) is not limited to these. Further, some of these compounds have an asymmetric carbon atom in the molecule. Needless to say, not only the dl-form but also any optically active form is included. (1) isoprenyl alcohol [alias: 3-methyl-2-buten-1-ol] (2) isoprenyl chloride [alias: 1-chloro-3-methyl-2-butene] (3) isoprenyl bromide [alias; 1-bromo-3-methyl-2-butene] (4) isoprenyl iodide [alias; 1-iodo-3-methyl-2-
Butene] (5) 3,7-dimethyl-2-octen-1-ol (6) 1-chloro-3,7-dimethyl-2-octene (7) 1-bromo-3,7-dimethyl-2-octene (8) 1-iodo-3,7-dimethyl-2-octene (9) 3,7,11-trimethyl-2-dodecene-1-ol (10) 1-chloro-3,7,11-trimethyl-2 -Dodecene (11) 1-bromo-3,7,11-trimethyl-2-dodecene (12) 1-iodo-3,7,11-trimethyl-2-dodecene (13) phytol (14) phytyl chloride (15) Phytyl bromide (16) Phytyl iodide (17) Phytyl acetate (18) Phytyl methanesulfonate (19) Phytyl toluenesulfonate (20) 3,7,11,15,19-Pentamethyl-2-icosen-1-ol (21) 1-chloro-3,7,11,15,19-pentamethyl-2-icocene (22) 1-bromo-3,7,11,15,19-pentamethyl-2-icocene (23) 1-iodo -3,7,11,15,19-pentamethyl-2-icosene (24) 3,7,11,15,19,23-hexamethyl-2-tetracocene-1
-All (25) 1-chloro-3,7,11,15,19,23-hexamethyl-2-tetracocene (26) 1-bromo-3,7,11,15,19,23-hexamethyl-2-tetracocene (27) 1-iodo-3,7,11,15,19,23-hexamethyl-2-tetracocene

Next, the alkenyl alcohol (III) in the present invention is represented by the following general formula.

[0019]

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In the formula, n has the same meaning as described above. More specifically, the following compounds can be mentioned,
The alkenyl alcohol (III) in the present invention is not limited to these. Further, some of these compounds have an asymmetric carbon atom in the molecule. Needless to say, not only the dl-form but also any optically active form is included. (1) 2-methyl-3-buten-2-ol (2) 3,7-dimethyl-1-octen-3-ol (3) 3,7,11-trimethyl-1-dodecene-3-ol (4 ) Isophytol (5) 3,7,11,15,19-pentamethyl-1-icosen-3-ol (6) 3,7,11,15,19,23-Hexamethyl-1-tetracocene-3-
Oar

Subsequently, the α-tocopherol derivative (IV) according to the present invention is represented by the following general formula.

[0022]

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In the formula, n has the same meaning as described above. More specifically, the following compounds can be mentioned,
The α-tocopherol derivative (IV) in the present invention is not limited to these. Furthermore, some of these compounds have an asymmetric carbon atom in the molecule.
It goes without saying that both optically active substances are included. (1) 3,4-dihydro-2,5,7,8-tetramethyl-2-methyl-2H-
1-benzopyran-6-ol (2) 3,4-dihydro-2,5,7,8-tetramethyl-2- (4-methylpentyl) -2H-1-benzopyran-6-ol (3) 3, 4-dihydro-2,5,7,8-tetramethyl-2- (4,8-dimethylnonyl) -2H-1-benzopyran-6-ol (4) α-tocopherol (5) 3,4-dihydro- 2,5,7,8-tetramethyl-2- (4,8,12,16
-Tetramethylheptadecyl) -2H-1-benzopyran-6-ol (6) 3,4-dihydro-2,5,7,8-tetramethyl-2- (4,8,12,1
(6,20-pentamethylhenicosyl) -2H-1-benzopyran-6-
Oar

Finally, zinc iodide used as a catalyst in the present invention is commercially available as a reagent or an industrial raw material.
It is readily available. However, a method for producing an α-tocopherol derivative (IV) using zinc iodide as a catalyst has not been known at all. In the present invention,
Generate zinc iodide from general-purpose raw materials in the reaction system,
It is also possible to produce the α-tocopherol derivative (IV) using it as a catalyst.

Next, the production method according to the present invention will be described in detail below. This production method can be carried out according to a conventional method of Friedel Crafts reaction, but usually, trimethylhydroquinone (I) and a catalyst (zinc iodide) are mixed, and a solvent is added or a solvent is added if necessary. About 0.9 to 1.1 equivalents of allyl alcohol derivative (II) or alkenyl alcohol (III) are added relative to trimethylhydroquinone (I). The reaction is preferably performed in a stream of inert gas such as nitrogen or argon, but is not necessarily limited.

The amount of the catalyst (zinc iodide) used in the present invention is not limited either, but is usually 0.1 to 2.0 equivalents, preferably 0.2 to 1.5 equivalents, more preferably 0.3 to 1.5 equivalents to trimethylhydroquinone (I). Use 0.8 equivalents. Also, in the reaction system, when zinc iodide is produced from zinc chloride or zinc bromide, which is a general-purpose raw material, similarly, these are used in an amount of 0.1 to 2.0 equivalents per 1 g of trimethylhydroquinone (I), preferably 0.2 to 1.5. Equivalent, more preferably 0.3
Use ~ 0.8 equivalents.

In the reaction system, when zinc iodide is produced from zinc chloride or zinc bromide, which is a general-purpose raw material,
It can be derived from zinc chloride or zinc bromide and hydrogen halide and sodium or potassium iodide. Here, as the hydrogen halide, usually, hydrogen chloride, hydrogen bromide or hydrogen iodide can be used. These are not limited to gas or aqueous solution, but usually use concentrated hydrochloric acid / concentrated brominated acid / concentrated hydroiodic acid from the viewpoint of workability. Among these combinations, zinc chloride, hydrogen chloride, hydrogen bromide or hydrogen iodide, and sodium iodide are more preferable from the viewpoint of suppression of by-products of impurities and economy.

The amount of hydrogen halide used is not limited, but is usually 0.01 to 1.5 equivalents, preferably 0.05 to 1.0 equivalent, more preferably zinc chloride or zinc bromide.
Use 0.1-0.5 equivalents.

Although the amount of sodium iodide or potassium iodide used is not limited, it is usually 0.1 to 3.0 equivalents, preferably 0.3 to 2.0 equivalents to zinc chloride or zinc bromide.
More preferably, 0.6 to 1.5 equivalents are used.

In the present invention, the reaction can be carried out without a solvent, but a solvent is preferably used. When used, the solvent is not limited as long as it is a solvent that is inert to trimethylhydroquinone (I), allyl alcohol derivative (II), alkenyl alcohol (III), zinc iodide, zinc chloride, zinc bromide and the like. Specific examples include, for example, benzene, toluene, xylene, nitrobenzene, chlorobenzene, dichlorobenzene, nitromethane, tetrahydrofuran, 1,2-dimethoxyethane, ethyl ether, isopropyl ether, butyl ether, methyl acetate, ethyl acetate, propyl acetate, methyl propionate, Ethyl propionate, methyl butyrate, ethyl butyrate, dimethyl carbonate,
Diethyl carbonate, dipropyl carbonate, methyl ethyl carbonate, acetone, 2-butanone (methyl ethyl ketone), 3-pentanone (diethyl ketone), 3-hexanone (ethyl propyl ketone), 4-heptanone (dipropyl ketone), 2,4-dimethyl -3-pentanone (diisopropyl ketone), propyl alcohol, butyl alcohol, pentanol, t-amyl alcohol, hexane, octane, decane, decalin, cyclohexane, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1, 1,1-trichloroethane, 1,1,2-trichloroethane, tricrene, 1,1,1,2-tetrachloroethane, 1,1,2,
2-tetrachloroethane, 1-chloropropane, 2-chloropropane, 1,1-dichloropropane, 1,2-dichloropropane, 1,3-dichloropropane, 2,2-dichloropropane, 1,
Examples thereof include 4-dioxane, 1,3-dioxolane, and the like. Xylene, ethyl acetate, 2-
Butanone, propyl alcohol, n-hexane, octane, cyclohexane or nitromethane.

The amount of the solvent used is not limited, but usually 0.5 to 100 ml per 1 g of trimethylhydroquinone (I),
Preferably 0.7 to 50 ml is used, more preferably 1 to 20 ml. The solvent may be used alone, or a mixture of two or more kinds may be used.

The reaction temperature in the present invention is from under cooling to room temperature.
The reaction can be carried out at a solvent reflux temperature or under heating, but it is usually preferable to heat or reflux under heating at about 30 to 100 ° C. in order to shorten the reaction time. When heating or refluxing at about 30 to 100 ° C., the reaction is usually completed in about 1 to 12 hours. The reaction time can be further shortened by azeotropic dehydration using an appropriate solvent.

The α-tocopherol derivative (I
V) can be purified by a conventional method such as silica gel column chromatography, HPLC, and molecular distillation.

Next, the present invention will be described in detail with reference to Examples and Comparative Examples, but it goes without saying that the present invention is not limited thereto. In each example, GLC analysis was performed under the following conditions.

(1) GLC analysis conditions Column; BPX-5 Column temperature; 170 ° C. → 5 ° C./min→230° C. → 10 ° C./min→290
℃ → 5 ℃ / min → 350 ℃ (15min) Inlet temperature; 350 ℃ Detector temperature; 350 ℃ Flow rate; 1.8ml / min Sample injection volume; 1μl Split ratio; 1:20

(2) Preparation method of measurement sample A 300 mg sample was weighed in a 10 ml volumetric flask, and the volume was adjusted with ethanol.

[0037]

EXAMPLES Example 1 Synthesis of α-Tocopherol

[0038]

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22.8 g of trimethylhydroquinone (TMH) (0.15
mol), zinc chloride 13.6 g (0.10 mol), sodium iodide 30.0 g (0.20 mol), and concentrated hydrobromic acid 4.05 g (0.024 mol) were suspended in diethyl carbonate (60 ml) and heated to 50 ° C. To this, 47.4 g (0.16 mol) of isophytol (IP) was added dropwise over 90 minutes. The reaction was continued for another hour. After cooling,
The reaction solution was washed with water several times, and dried over magnesium sulfate. The organic phase was concentrated under reduced pressure to give the title compound as a brown oil (66.4 g)
I got (Yield: 100%, GLC purity: 98.04%, impurity content: 0.24%)

The following results were obtained in the same manner as in Example 1. (In the table, C-HX means concentrated hydrohalic acid, and impurities mean the impurities represented by the above [Chemical Formula 8].) No. ZnCl ₂ C-HX NaI GLC purity Impurity 1 13.6 g 48% HBr 4.05g 30.0g 98.04% 0.24% 0.10mol 0.024mol 0.20mol 2 Same as above 57% HI 5.39g Same as above 97.81% 0.24% 0.024mol 3 Same as above 37% HCl 2.36g Same as above 98.11% 0.30% 0.024mol 4 Same as above 48% HBr 4.05g 15.0 g 96.96% 0.40% 0.024mol 0.10mol 5 12.3g Same as above 27.0g 96.96% 0.28% 0.09mol 0.18mol 6 10.3g Same as above 22.5g 96.70% 0.29% 0.075mol 0.15mol

Comparative Examples 7 and 8 Synthesis of α-Tocopherol Subsequently, as a comparative example, the results shown in the following table were obtained without using sodium iodide in the same manner as in Example 1. No. ZnCl ₂ C-HX NaI GLC purity Impurity 7 13.6 g 48% HBr 4.05 g None 96.21% 0.92% 0.10mol 0.024mol 8 Same as above 57% HI 5.39g None 97.03% 0.72% 0.024mol 9 Same as above 37% HCl 2.36g None 95.68% 1.03% 0.024mol

From the above Examples and Comparative Examples, the production method according to the present invention significantly reduces the amount of impurities that cannot be removed by the ordinary purification method, and is suitable for pharmaceuticals, foods, cosmetic raw materials, etc., which require extremely high purity. Excellent effect is evident.

[Brief description of the drawings]

FIG. 1 is a GLC analysis chart of α-tocopherol obtained in Comparative Example 9, wherein a retention time of 18.6 minutes is an impurity peak.

Claims (4)

[Claims] 1. A trimethylhydroquinone (I) represented by the following chemical formula: Allyl alcohol derivative (II) represented by the following general formula: [In the formula, n represents an integer of 0 to 1 and L represents a hydroxyl group, a halogen atom, an acetoxy group, a methanesulfonyloxy group, an ethanesulfonyloxy group, a benzenesulfonyloxy group, or a toluenesulfonyloxy group. Or an alkenyl alcohol (III) represented by the following general formula: [Wherein, n has the same meaning as described above. The α-tocopherol derivative (IV) represented by the following general formula, wherein the condensation reaction is carried out in the presence of zinc iodide.
Manufacturing method. Embedded image Wherein n has the same meaning as described above. ] 2. The method according to claim 1, wherein the zinc iodide is derived from zinc chloride or zinc bromide and hydrogen halide and sodium or potassium iodide in the reaction system.
A method for producing the α-tocopherol derivative (IV) according to claim 1. 3. The method for producing an α-tocopherol derivative (IV) according to claim 1, wherein the hydrogen halide is hydrogen chloride, hydrogen bromide or hydrogen iodide. 4. Zinc iodide is combined with zinc chloride in a reaction system.
4. The method for producing an α-tocopherol derivative (IV) according to claim 1, which is derived from hydrogen chloride, hydrogen bromide or hydrogen iodide, and sodium iodide.