JP3482618B2 - Method for producing α-tocopherol derivative - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to antifertility vitamins, blood lipid lowering agents, blood flow enhancers, active oxygen scavengers, cell aging inhibitors, antioxidants and the like. The present invention relates to a method for producing a useful α-tocopherol derivative (IV). [0002] Heretofore, α-tocopherol derivatives (IV) have been
And trimethylhydroquinone (I) represented by the following chemical formula: Any of the phytols represented by the following chemical formula: Has been produced by condensation by Friedel-Crafts reaction. [0007] 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 yield, product purity, operability, price, and the like. Problems to be Solved by the Invention Conventionally, zinc chloride used as a catalyst in a process for producing an α-tocopherol derivative (IV) is stoichiometric with respect to trimethylhydroquinone (I) or phytols. It is preferable to use about equivalent weight of the catalyst, and even though the catalyst is used, it has a large economical disadvantage because it accounts for a large proportion of the production cost, and there is also a problem that the reaction volume and the amount of waste disposal increase. In addition, hydrochloric acid, sulfuric acid,
It was preferred to use a protic acid such as phosphoric acid as the cocatalyst. Further, when zinc chloride is used as a catalyst, usable solvents are often limited, and alcohol solvents cannot be used. As described above, the conventional method for producing an α-tocopherol derivative (IV) using zinc chloride as a catalyst has many problems in economy, operability, waste disposal, and the like. An excellent catalyst was desired. [0011] Therefore, the present inventors have intensively studied to improve the above-mentioned problems of the conventional catalyst. As a result, by using zinc bromide as a catalyst, the intended purpose was achieved and the α-tocopherol derivative (I
The present inventors have found that V) can be produced industrially and completed the present invention. Accordingly, an object of the present invention is to provide an anti-fertility vitamin,
An object of the present invention is to provide an industrially excellent production method of an 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. The allyl alcohol derivative (I) according to the present invention
I) is represented by the following general formula. Embedded image 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, a fluorine atom and the like. More specifically, the following compounds can be exemplified. Derivative
(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 [also known as 1-chloro-3-methyl-2-butene] (3) isoprenyl bromide [also known as 1-bromo-3-methyl-2-butene] (4) Isoprenyl iodide [also known as 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) vinegar Phytyl (18) phytoyl methanesulfonate (19) phytyl (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-Icocene (24) 3,7,11,15,19,23-hexamethyl-
2-tetracosen-1-ol (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. You. Embedded image 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-tetracosen-3-ol Subsequently, the α-tocopherol derivative (IV) according to the present invention is represented by the following general formula. Embedded image 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-tetramethyl Heptadecyl) -2H-1-benzopyran-6-ol (6) 3,4-dihydro-2,5,7,8-tetramethyl-2- (4,8,12,16,20-pentamethylhexico Sil) -2H-1-benzopyran-6-ol Finally, as a catalyst in the present invention, Zinc bromide which are are commercially available as reagents or industrial raw materials, are readily available. However, a method for producing an α-tocopherol derivative (IV) using zinc bromide as a catalyst has not been known at all. Next, the production method according to the present invention will be described in detail below. This production method can be carried out according to the usual method of the Friedel-Crafts reaction, but usually, trimethylhydroquinone (I) and a catalyst are mixed, and a solvent is added without a solvent or as necessary, and trimethylhydroquinone is added thereto.
About 0.9 to 1.1 equivalents of the allyl alcohol derivative based on (I)
(II) or alkenyl alcohol (III) is added. The reaction is preferably performed in a stream of inert gas such as nitrogen or argon, but is not necessarily limited. 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 inert to trimethylhydroquinone (I), allyl alcohol derivative (II) or alkenyl alcohol (III) or zinc bromide. 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, 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, Roform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, tricrene, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetra Chloroethane, 1-chloropropane,
Examples thereof include 2-chloropropane, 1,1-dichloropropane, 1,2-dichloropropane, 1,3-dichloropropane, 2,2-dichloropropane, 1,4-dioxane, and 1,3-dioxolan. , Preferably methylene chloride, chloroform, carbon tetrachloride, dichloroethane, trichloroethane,
Benzene, toluene, xylene, ethyl acetate, 2-butanone, propyl alcohol, n-hexane, octane, cyclohexane or nitromethane. The amount of the solvent to be used is not limited, but usually about 0.5 to 100, preferably about 0.7 to 50, more preferably about 1 to 20 with respect to trimethylhydroquinone (I). The solvent may be used alone, or a mixture of two or more kinds may be used. Furthermore, co-catalysts such as hydrochloric acid, sulfuric acid and phosphoric acid are not required. Although the amount of the catalyst used in the present invention is not limited, it is usually about 0.01 to 1.5 equivalents, preferably about 0.05 to 1.0 equivalent, more preferably about 0.1 to 0.5 equivalent based on trimethylhydroquinone (I). Use As described above, in the method of the present invention, it is not necessary to use a stoichiometrically equivalent amount of the catalyst as in the conventional method. Further, in the present invention, there is an advantage that a cocatalyst such as hydrochloric acid, sulfuric acid, and phosphoric acid is not required. The reaction temperature in the present invention may be from room temperature to the reflux temperature of the solvent or under heating.
It is preferable to heat or reflux under heating at about 100 ° C. in order to shorten the reaction time. When heating or refluxing at about 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 produced 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 more detail with reference to the following examples. However, it goes without saying that the present invention is not limited to these examples. EXAMPLES Example 1 Synthesis of α-Tocopherol 23.3 g (0.15 mol) of TMH and 15.8 g (0.0
7 mol), propyl alcohol (12.7 ml) and toluene (47.5
ml), and the mixture was heated under reflux for 5 minutes. Under reflux with heating, 47.4 g (0.16 mol) of isophytol was added dropwise over 3 hours. The reaction was continued for another 8.5 hours.
After cooling, hexane was added, washed with water, washed with a 1N aqueous solution of sodium hydroxide, washed with water, and the organic phase was dried over magnesium sulfate. The organic phase was concentrated under reduced pressure to give the title compound as a brown oil.
66.4 g were obtained. (Yield; 100%, GLC purity; 95.2%) Reference Example 2 Synthesis of α-tocopherol 23.3 g (0.15 mol) of TMH and zinc bromide 1
5.8 g (0.07 mol) of 2-butanone (12.
7ml) and toluene (45.7ml).
The mixture was refluxed for 5 minutes. Under reflux with heating, 47.4 g (0.16 mol) of isophytol was added dropwise over 4 hours. The reaction was continued for another 6.5 hours. After cooling, hexane was added, washed with water, washed with a 1N aqueous solution of sodium hydroxide, washed with water, and the organic phase was dried over magnesium sulfate. The organic phase was concentrated under reduced pressure to give the title compound 6 as a brown oil.
5.5 g were obtained. (Yield; 99.5%, GLC purity;
Examples 3 to 6 Synthesis of α-tocopherol 2.9 g (0.019 mol) of TMH was suspended in a solvent, and zinc bromide was added at room temperature.
2.15 g (0.0095 mol) were added. Then isophytole 5.93
g (0.020 mol) was added dropwise at 70 ° C. over 15 minutes. The mixture was heated under reflux for 6 hours, cooled, added with toluene, washed with a 1N aqueous solution of sodium hydroxide and a saturated saline solution in that order, and the organic phase was dried over magnesium sulfate. The organic phase was concentrated under reduced pressure to give the title compound as a brown oil, as shown in the table below. [Table 1]

Continuation of the front page (72) Inventor Chiaki Seki 216-150 Kubo Isshiki, Komaki City, Aichi Prefecture (56) References JP-A-59-62582 (JP, A) JP-A-51-80859 (JP, A) (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 311/72 CA (STN)

Claims (1)

(57) [Claims 1] Trimethylhydroquinone (I) represented by the following chemical formula: And an allyl alcohol derivative represented by the following general formula (I
I) [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 represented by the following general formula (I
II) [Wherein, n has the same meaning as described above. Propyl alcohol, butyl alcohol
Alcohol, pentanol and t-amyl alcohol
Using one or more alcohol solvents selected from the group
And about 0.1 to 0.1 with respect to trimethylhydroquinone.
A method for producing an α-tocopherol derivative (IV) represented by the following general formula, which is carried out in the presence of 5 equivalents of zinc bromide. Embedded image [Wherein, n has the same meaning as described above. ]