JPH07107994A - Production of optically active alpha-tocopherol compound - Google Patents

Abstract

PURPOSE:To simply obtain a high-purity optically active alpha-tocopherol compound in good yield by subjecting a specific alpha-tocopherol compound to aymmetric hydrolysis with an enzyme. CONSTITUTION:An alpha-tocopherol compound of formula I (R1 is aminooxalyl; R2 is alkyl other than methyl or alkyl having a substituent group) is subjected to asymmetric hydrolysis with an enzyme to prepare the objective alpha-tocopherol compounds of formula II and formula III (* is optically active point). As the enzyme, a lipase derived from a microorganism which belongs to the genus Candida, e.g. 'LIPASE AY<(>R<)>' (derived from Candida rugosa and manufactured by Amano Pharmaceutical Co., Ltd.) or 'LIPASE OF<(>R<)>' (derived from Candida cylindracea and manufactured by Meito Sangyo Co., Ltd.), etc., is exemplified. The reaction is normally carried out in an organic solvent containing water at 0-40 deg.C for 1-120hr.

Description

Detailed Description of the Invention

[0001]

Industrial field α-Tocopherol (vitamin E) has a strong antioxidant effect and is useful as a scavenger of active oxygen species which is one of the causes of causing harm to human body, especially carcinogenesis. It has been found to be.

[0002]

2. Description of the Prior Art Most of the α-tocopherols currently used are synthetic products and are a mixture of eight isomers in which all three asymmetric carbon atoms are racemic.

For the activity of vitamin E, the stereochemistry at the 2-position of the chroman ring is important. The synthesis of the optically active substance at the 2-position was performed by the resolution of the piperazine salt of Robeson et al. [J. Am. Chem. Soc., 84 , 3
196 (1962)] and 3-Bromo-campher-8-sulfo by Karrer et al.
Split as nate [Helv. Chem. Acta., 46 , 333 (1963)]
Has been reported.

A method for asymmetrically hydrolyzing the acetate of α-tocopherol in the presence of bile using cholesterol esterase [J. Am. Chem. Soc., 113 , 2797 (1
991)] has been reported. However, in this method, regarding the asymmetric hydrolysis at the 2-position, only the difference in reaction rate is shown, and the optical purity of the actually obtained product is not described. Further, since it contains an amphipathic substance such as bile, the post-treatment becomes difficult, which is not an industrial method.

[0005]

The above-mentioned conventional methods are complicated in operation and poor in yield, and the optical purity is not satisfactory, and it has been desired to develop a method with a higher yield. . As a result of diligent studies, the present inventor found a useful method capable of obtaining an optically active substance with extremely high purity by an asymmetric hydrolysis reaction using an enzyme.

[0006]

As a result of studying a more practical method, the present invention has the general formula [IV]

[0007]

[Chemical 4]

In the case where R ₃ , R ₄ and R ₅ are methyl groups, R ₁ is an aminooxaryl group, that is, the following general formula [I]

[0009]

[Chemical 5]

It was found that an optically active substance having a high optical purity can be obtained by carrying out asymmetric hydrolysis with an enzyme using the compound as a substrate, and that this method is industrially useful. The present invention has been completed.

That is, an α-tocopherol compound suitable as a substrate for asymmetric resolution by a hydrolase is represented by the general formula
[I]

[0012]

[Chemical 6]

[In the formula, R ₁ represents an aminooxalyl group, and R ₂ represents an alkyl group other than a methyl group or an alkyl group having a substituent. ] Stereoselectively hydrolyzing using an α-tocopherol compound represented by the general formula [II]

[0014]

[Chemical 7]

And the general formula [III]

[0016]

[Chemical 8]

[In the formula, R ₁ represents an amino oxalyl group, R ₂ represents an alkyl group other than a methyl group or an alkyl group having a substituent, and * represents an optically active point. ] The α-tocopherol compound represented by the following formula was produced, and the asymmetric yield and the reaction efficiency were both satisfactory.

The present invention will be described in detail below. In the compounds represented by the general formulas [I], [II] and [III], R ₁ is an amino oxalyl group, for example, an amino oxalyl group, a dimethyl-amino oxalyl group, a diethyl-amino oxalyl group, etc., and R ₂ is a methyl group. It is an alkyl group other than the group (for example, 4,8,12-trimethyltridecyl group, 4,8-dimethylnonyl group, 4-methylpentyl group, etc.).

As the enzyme used in the present invention, the optically active α-tocopherol compound represented by the above general formulas [II] and [III] is produced from the prochiral α-tocopherol compound represented by the above general formula [I]. Any enzyme may be used as long as it has an activity to cause it, but specifically, lipase derived from a microorganism belonging to the genus Candida, for example, lipase AY (trade name: manufactured by Amano Pharmaceutical Co., Candida rugosa), lipase OF (trade name) : Made by Meito Sangyo, Candida cyli
ndracea) etc. can be used. The enzyme used may be a crude product or a purified product. In addition, bacterial cells that produce these enzymes can also be used.

The reaction of the present invention is usually 1 to 120 at 0 to 40 ° C.
It is preferable to carry out the reaction for a time so that the enzyme is dispersed in the reaction system. Further, such a lipase may be used as it is, or may be fixed to an appropriate carrier and used as an immobilization reactor.

The reaction of the present invention is usually carried out in an organic solvent containing water. The organic solvent used is not particularly limited, but examples thereof include isopropyl ether, cyclohexane, chloroform, benzene, acetone, acetonitrile and the like. More preferably, water saturated isopropyl ether or water saturated cyclohexane is used. After completion of the reaction, the enzyme can be easily removed by a conventional method, for example, by filtration using filter paper. The reaction product is, for example, chloroform when a large amount of water is contained,
It can be extracted and separated with benzene, diethyl ether, etc. Furthermore, the reaction product can be easily purified by using, for example, silica gel column chromatography.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

[0023]

【Example】

Example 1 Synthesis of tocopherol oxalyl diethyl amide 3 ml of oxalyl chloride was dissolved in 5 ml of THF, and dl
-Tocopherol 1.4g (3.3mmol) is added and stirred at room temperature for 1 hour. The THF and excess oxalyl chloride were distilled off well, the residue was again dissolved in 5 ml of THF, and then 3 ml of aqueous ammonia was slowly added dropwise. The mixture is stirred at room temperature for 18 hours, 20 ml of ether and 20 ml of water are added, and the layers are separated. The extract was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel chromatography to obtain tocopherol oxalyl amide.

Yield: 320 mg (20%) ¹ H-NMR (CDCl ₃ ) δ: 0.83-0.88 (12H, m), 1.00-1.65 (24
H, m), 1.70-1.90 (2H, m), 2.05-2.15 (9H, m), 2.63 (2H, t, J
= 6Hz), 3.50 (2H, br).

Enzymatic asymmetric hydrolysis of tocopherol oxalyl amide Example 2 tocopherol oxalyl amide 100 mg obtained in Example 1
(0.21 mmol) is dissolved in water saturated isopropyl ether,
Add 100 mg of Lipase AY. After stirring at room temperature for 60 hours, filter to remove the enzyme and concentrate. Separation and purification by silica gel chromatography (methylene chloride) gave optically active (2R) -tocopherol oxalyl amide 28 mg (yield = 2
8%, 81% ee) and (2S) -tocopherol 55 mg (yield = 61%, 4
8% ee).

Example 3 Tocopherol obtained in Example 1 in the same manner as in Example 2
100 mg (0.21 mmol) of xalyl amide is dissolved in isopropyl ether saturated with water, and 100 mg of lipase OF is added. After stirring at room temperature for 60 hours, filter to remove the enzyme and concentrate. Separated and purified by silica gel chromatography (methylene chloride) to obtain optically active (2R) -tocopherol oxalyl ami
de 41mg (Yield = 41%, 80% ee) and (2S) -tocopherol 44m
g (yield = 48%, 55% ee) was obtained.

[0027]

INDUSTRIAL APPLICABILITY According to the present invention, a novel method has been found in which many vitamin E conventionally developed as a racemate and used as a medicine are developed as an optically active substance and used for medical treatment.

Claims (1)

[Claims] 1. A compound represented by the general formula [I]: [In the formula, R ₁ represents an aminooxalyl group, and R ₂ represents an alkyl group other than a methyl group or an alkyl group having a substituent. ]
An enzyme acts on the α-tocopherol compound represented by the general formula [II] And the general formula [III] [In the formula, R ₁ represents an aminooxalyl group, R ₂ represents an alkyl group other than a methyl group or an alkyl group having a substituent, and * represents an optically active point. ] The method of manufacturing the alpha-tocopherol compound represented by these.