JPS636054B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing lignans, particularly allyltetrahydronaphthalide type lignans.

Allyltetrahydronaphthalide type lignans represented by the general formula () are useful as compounds having antibacterial activity.

Conventionally known methods for producing lignans include:
There are many known methods for extracting and refining these compounds from plants containing them using lower hydrocarbons such as petroleum ether or solvents such as ether, as well as many synthetic methods. Various synthetic methods have been reported, but since lignans are thought to be biosynthesized by oxidative coupling of parahydroxyphenylpropene units, there are many synthetic studies that mimic biosynthesis. .

A simple classification of these synthesis methods is the method of oxidizing parahydroxyphenylpropene with metal salts such as iron [KJSarkanen et al., J.Chem.
Soc. Perkin, 1869 (1973)], Method of electrolytic oxidation of para-hydroxyphenylpropene [S.
Yamahara et al., Bull.Chem.Soc.Japan 49 ,
1940 (1976); M Iguchi et al., Tetrahedron
Lett., 4511 (1977)], Method using quinone intermediate obtained by oxidation of phenol [G.Bu¨chi
et al., J.Amer.Chem.Soc., 99 8073 (1977)].

The present inventors conducted intensive research on a method for synthesizing lignans with high yield and simple operation, and found that phenylpropenes were dissolved in acetonitrile, and chromic anhydride was dissolved in a strong acid and acetonitrile. By oxidizing using an oxidizing composition, the general formula () can be obtained in one step and in high yield.
They discovered that a compound represented by the formula can be produced, and completed the present invention.

In the present invention, the compound represented by the general formula () used as a starting material is, for example, a methoxy group,
Ethoxy group, propoxy group, isopropoxy group,
Benzaldehydes substituted with a lower alkoxy group such as n-butoxy group, isobutoxy group, sec-butoxy group, t-butoxy group, or substituted with methylenedioxy group or ethylenedioxy group are mixed with Wittig reagent or the like. It can be easily obtained by reacting and elongating the carbon chain.

Next, the oxidizing composition used in the oxidation reaction can be obtained by dissolving chromic anhydride in a strong acid and acetonitrile at room temperature or at a temperature below the boiling point of acetonitrile, preferably at room temperature. Examples of strong acids that can be used in this oxidizing composition include HBF ₄ , H ₂ SO ₄ , and HClO ₄ , and those containing water are more preferred.

The reaction is carried out by dissolving the compound represented by the general formula () in acetonitrile, and adding thereto the above-mentioned oxidizing composition in which chromic anhydride is dissolved in a strong acid and acetonitrile. In this case, the reaction can be carried out at room temperature or by heating to within the boiling point of the organic solvent, but it is preferable to carry out the reaction at room temperature. The reaction is complete when the solution turns from yellow to green, usually in 1-2 minutes. Immediately after the reaction is complete, add an appropriate amount of water to the reaction solution, add ether,
Extract several times with organic solvents such as ethyl acetate, chloroform, methylene chloride, petroleum ether, n-hexane, benzene, toluene, etc., combine the extracts, and add a commonly used desiccant such as anhydrous sodium sulfate to this extract. Remove water from the solution.
This solution is filtered and the solvent is distilled off from the filtrate to obtain a residue. This residue is subjected to column chromatography using an adsorbent such as silica gel or alumina, preparative thin layer chromatography, or
The compound represented by the general formula () can be obtained by purifying it by conventional separation and purification techniques such as high-performance liquid chromatography using normal-phase or reverse-phase carriers, and further purifying it by recrystallization. can be obtained.

In the above reaction, the benzyl position of the compound represented by the general formula () is oxidized, a hydroxyl group is introduced, and at the same time, two molecules are coupled to form a six-membered ring, and the hydroxyl group is further oxidized to become a ketone. A compound represented by the formula () is produced.

Therefore, since this reaction proceeds in the propenyl group of the side chain of the compound represented by the general formula (), the substituent R ₁ on the benzene ring,
The reaction proceeds in the same manner regardless of whether R ₂ or R ₃ is any of the above.

The advantages of the present invention include the following points, and these advantages show that the present invention is superior to conventional methods for producing lignans.

According to the present invention, the desired lignans represented by the general formula () can be obtained in one step from the phenylpropanes represented by the general formula ().

In the present invention, the oxidation reaction rate is extremely fast (the reaction usually completes in 1 to 2 minutes) and the reaction operation is easy.

In the present invention, the end of the reaction can be determined by a change in the color of the reagent (change from yellow to green).

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 Dissolve 2.14 g of 3,4-dimethoxyphenylpropene (1), which can be easily obtained by extending the carbon chain by reacting commercially available 3,4-dimethoxybenzaldehyde with Wittig reagent, in 10 ml of acetonitrile, and add anhydrous chromium to the solution. An oxidizing composition prepared from 1.33 g of acid, 27 ml of 40% HBF ₄ aqueous solution, and 120 ml of acetonitrile is added at room temperature with stirring. The reaction solution changes from yellow to green in 1 to 2 minutes. water immediately
Add 100 ml and extract 3 times with 50 ml of ether. The extracts are combined, dried over anhydrous sodium sulfate, the desiccant is removed, and the solvent is distilled off. The residue was subjected to column chromatography using 50 g of silica gel as an adsorbent and eluted with a mixed solvent of n-hexane and chloroform. Recrystallized from n-hexane-ether to obtain 0.55 g of allyltetrahydronaphthalide-type lignan derivative (2) in the form of colorless needles (yield 51%).
Obtained. The molecular formula and properties of the compound (2) thus obtained are as follows, and from this, it was confirmed that this compound has the structural formula represented by formula (2).

Melting point: 124-126℃ Molecular formula: C ₂₂ H ₂₆ O ₅ High mass spectrum: Theoretical value (M ⁺ ) 370.1779 Experimental value (M ⁺ ) 370.1793 Infrared absorption spectrum ν ^nujol _nax cm ^-1 : 1680, 1660 Nuclear magnetic resonance spectrum ( δin CDCl ₃ ): 0.98 (3H,
d, J = 6, 1Hz), 1.18 (3H, d, J = 6.6
Hz), 2.46-2.89 (1H, m), 3.15-3.31 (1H,
m), 3.90 (6H, s), 3.94, 3.95 (3H, s each),
6.73-6.92 (4H, m), 7.57 (1H, s) Example 2 19 g of 3,4,5-trimethoxyphenylpropene (3), which is easily obtained by carbon extension by reacting commercially available 3,4,5-trimethoxybenzaldehyde with Wittig reagent, was added to acetonitrile.
Dissolve in 600ml and add 10g of chromic anhydride, 40%
Add an oxidizing agent prepared with 320 ml of HBF ₄ water and 600 ml of acetonitrile while stirring at room temperature. After completion of the reaction (2 minutes), add 500 ml of water, extract 4 times with 300 ml of ether, combine the extracts, and dry over anhydrous sodium sulfate. After removing the sodium succinate, the solvent is distilled off.

The residue was subjected to column chromatography using 100 g of silica gel as an adsorbent, and eluted with a mixed solvent of n-hexane and chloroform. Allyltetrahydronaphthalide type lignan derivative (4) was obtained by recrystallization from a mixed solvent of n-hexane and ether.
2.8 g (yield 29.5%) is obtained. The molecular formula and properties of compound (4) thus obtained are described below.

Colorless needle crystal Melting point: 135-137℃ Molecular formula: C ₂₄ H ₃₀ O ₇ High mass spectrum: Theoretical value (M ⁺ ) 430, 1990 Experimental value (M ⁺ ) 430, 2016 Infrared absorption spectrum ν ^nujol _nax cm ^-1 : 1690 , 1595 Nuclear magnetic resonance spectrum (δin CDCl ₃ ): 1.10 (3H,
d, J = 6.4Hz) 1.16 (3H, d, J = 6.6Hz) 1.18-2.00 (1H, m) 2.32-2.95 (1H, m) 3.14 (3H, s) 3.77, 3.81, 3.82, 3.92 (15H, s) 6.29 (2H, s) 7.33 (1H, s)

Claims (1)

[Claims] 1 General formula () [In the formula, R ₁ , R ₂ and R ₃ are the same or different and represent a hydrogen atom or a lower alkoxy group, or two of them taken together at the ortho position to each other represent a methylenedioxy group or an ethylenedioxy Indicates the group. However, at least one of the ortho positions to the propenyl group of the benzene ring shall not be a substituent other than a hydrogen atom. Further, the double bond of the propenyl group may be either cis or trans. ] Phenylpropenes represented by the general formula () are oxidized in acetonitrile by adding an oxidizing composition in which chromic anhydride is dissolved in a strong acid and acetonitrile. [In the formula, R ₁ , R ₂ and R ₃ have the same meaning as defined in the general formula (). ] A method for producing allyltetrahydronaphthalide-type lignans represented by