JPS6360944A - Optical resolution of lignans - Google Patents

Abstract

PURPOSE:To easily carry out optical resolution of the titled compound useful as pharmaceuticals, agricultural chemicals, etc., in high purity at a low cost on an industrial scale, by using an adsorbent composed mainly of a chemically stable polysaccharide ester which is available abundantly at a low cost. CONSTITUTION:A mixture of optical isomers of lignans is subjected to optical resolution by a chromatography such as gas chromatography, liquid chromatography, thin film chromatography, etc., using an adsorbent containing a polysaccharide derivative as an active component. The polysaccharide or its derivative is used in the form filled in a column as it is, supported on a carrier or coated on a capillary column in the case of liquid chromatography or gas chromatography. The particle size of the polysaccharide or its derivative is preferably 1mum-10mm. The most effective adsorbent is e.g. cellulose trisphenyl carbamate, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for isolating each enantiomer from a mixture of optical isomers (enantiomers) of lignans.

[Conventional technology and problems]

Optical isomers of asymmetric compounds usually have different physiological actions, and therefore, in medicines and agrochemicals, the use of only one enantiomer may eliminate side effects or improve the medicinal efficacy per unit. There is. Recently, studies have also begun to consider the use of optically active substances in liquid crystals and other optical materials. Under these circumstances, the synthesis or isolation of optically active substances is becoming an area of interest in organic synthetic chemistry.

The lignans targeted for optical resolution in the present invention are substances that exist as optically active substances in the tissues of various plants, and are often obtained as glycosides.

Many of these lignans or their glycosides have physiological activity, and some are considered to be active ingredients in Japanese and Chinese medicine, but their production volumes are small.

On the other hand, lignans can be used, for example, by oxidative coupling of alcohols having a skeleton represented by the following formula [Natural Product Chemistry, K., B., G. Thorsell.

Shigeo Nozoe, translated by Ushio Sanyo, PIOI~105 (1984)
) ; Chemistry of lignin - basics and applications, edited by Junzo Nakano, P
80-91 (1979)) or decomposition of lignin [Lignin chemistry - basics and applications, Junzo Nakano, P11
3-129 (1979)), the racemate can be obtained in large quantities. Therefore, if this can be optically resolved, a larger amount of dananes can be supplied, and if this is further subjected to a glycosylation reaction, lignan glycosides can be obtained.

However, there was no method to effectively optically resolve these lignans.

[Means for solving problems]

In view of the problems in producing liguna, ligna, or their glycosides as described in the previous section, the present inventors investigated a method of optical resolution that is simple and easy to industrialize. The present inventors have discovered that a separation method utilizing adsorption with an adsorbent containing as an active ingredient is suitable for the optical resolution of these compounds, and have completed the present invention.

That is, the present invention relates to a method for optically resolving lignans, which comprises optically resolving a mixture of optical isomers of lignans by chromatography using an adsorbent containing a polysaccharide derivative as an active ingredient.

The glue Dananes that are the subject of optical resolution in the present invention are:
The following (A), (B), (C) or (D) Ar
'-C-C-C l (A) Ar-C-C-C (Ar or Ar'' represents an aromatic ring residue. x7 is a single or multiple substituent, -011, -0CH3゜-0
-C11□-〇- etc. are common. n is 1 to 3
The n number of X's may be 0 and may be different from each other. ) is a group of compounds having a basic skeleton represented by however,
The present invention is limited to compounds having a cyclic structure containing an asymmetric center, regardless of whether they are natural or synthetic. That is, to be more specific, among compounds having a coumaran skeleton (C) and compounds having a so-called β-β bond (A), compounds having a cyclic structure as shown in the following (E) to (ri) Many are known to have it.

(E) (F) (G, Resinol bones (H) (I) (*
indicates an asymmetric center. ) Ar, Ar' may be any aromatic group, but (
Among natural lignans, the one shown in the following formula is common.

Specific examples of lignan compounds are listed below: nl Virginol (2) Sesamin (4) Medioresinol Epipyresinol CHz Podophyllotoxin (5) CR1 Deoxypodophyllotoxin H α-pertatin (Commentary on lignans; Junzo Nakano, Takamasa Hiro, Masayuki Sumimoto 9 Atsushi Ishizu "Wood Chemistry" Uni Publishing, 1982, Nobuhiko Migita, Yasumasa Yonezawa, Tamio Kondo) “Wood Chemistry” Volume 2, Kyoritsu Shuppan, 1972).

Many lignans have been found to have physiological activities such as pharmacological effects. Regarding this, W, D, Mc
Rae, G., 11. N.Towers, Phyto
Chemi-stry, 23.1207 (1984
) etc., so I will not go into details again, but I will give some examples. Glycosides of syringaresinol (1) are said to increase resistance to external stress and fatigue as an active ingredient of eleutherococcus, a tonic component extracted from Eleuthero. The glycoside of virginol (2) is derived from the Chinese herbal herb Euco++uwia.
ulmoides and is said to be effective for hypertension. Asarinin (3) has been shown to have an antituberculous effect, and together with its epimer, sesamin (4), has the effect of enhancing the efficacy of quilic acid insecticides. Podophyllotoxin (5) and its related substances are well known to have anti-UI activity. In addition, various physiological activities such as central nervous excitement, inhibition, cardiotonicity, and so on are frequently observed in various types of drugs. There are also some known examples in which the physiological activity differs between optical isomers.

Racemic forms of these lignans can be obtained by ordinary chemical synthesis, but in particular racemic forms of certain lignans can be obtained by converting the alcohol represented by the following formula into hydrogen peroxide in the presence of ferric ions or peroxidase. To oxidize (
References: V, 5arkanen, C, Il.

” d%4i g m + “Lignins”, P1
16-163 (1971), WileyInters
science ; Junzo Nakano "Chemistry of lignin - Basics and Applications -" P2O, 1974. K for 22 public relations; M, T
ana-hashi, H., Takeuchi, T.
Higuchi, Wood Res, +6L44~
53 (1976)), hydrolyzing lignin (
Ibid., "Lignins", P345-372 i Ibid., "Lignin Chemistry - Basics and Applications", pH 3-1
29; H, Naka-Lsubo, M, Ta
nahashi+ T, Iiguchi, Wo
od, Res, + 39-18 (1972)),
Also, in the so-called blasting process in which wood is treated with water and air under high temperature and pressure, and then rapidly returned to normal pressure to crush its structure, lignin decomposition products are produced (Tanahashi, Hiro, Gipa Gikyo Journal).

Sara, 118-127 (1985); same, Gipa Technology Times.

Kuni (7), 1-5 (1985); Tanahashi, Kobayashi, Higuchi, 35th Japan Wood Science Society, research presentation abstract, P288
(April 1985); Tanahashi, Hiro, 36th Japan Wood Society, Research Presentation Abstracts, P2O3 (April 1986)),
It is known that racemic lignans are produced in large quantities in each case.

The adsorbent used in the present invention contains polysaccharides and derivatives thereof as active ingredients. The polysaccharide referred to here is a synthetic polysaccharide,
Any optically active polysaccharide may be used, regardless of whether it is a natural polysaccharide or a polysaccharide modified from a natural product, but preferably a homoglycan with high regularity and a constant bonding pattern. More preferably, cellulose, amylose, β-1,4- from which highly purified polysaccharides can be easily obtained.
Chitosan, chitin, β-1,4-mannan, β-1,4
-xylan, inulin, α-1,3-glucan, β-L
3-glucan, etc. A polysaccharide derivative is one in which some or all, preferably 85% or more, of the hydrogen atoms on the hydroxyl groups of the polysaccharide are replaced with other atomic groups.

Examples of the atomic group here include a group represented by the following, where R1 is an aliphatic group having 1 to 3 carbon atoms, a cycloaliphatic group having 3 to 8 carbon atoms, and a cycloaliphatic group having 4 carbon atoms.
The mR form of these aromatic groups or heteroaromatic groups, each of which may have a substituent, can be easily obtained using various known chemical reactions. These polysaccharides and their derivatives are particularly suitable for industrial chromatographic separation because of their ease of raw material availability and stability. An example of the most effective adsorbent among these is cellulose trisphenyl rubbermate.

In the optical resolution method of the present invention, target lignans can be optically resolved by selecting an appropriate polysaccharide or derivative thereof from among these polysaccharides or derivatives thereof.

Examples of means for obtaining the optically active substance of the present invention using the above adsorbent include chromatography methods such as gas chromatography, liquid chromatography, and thin layer chromatography.

In order to use the adsorbent according to the present invention in a liquid chromatography method or a gas chromatography method, the polysaccharide or its derivative can be packed into a column as it is, held on a carrier and packed therein, or coated on a capillary column.

Since the adsorbent for chromatography is preferably in the form of particles, in order to use the polysaccharide or its derivative as an adsorbent for a compound, it is preferable to crush the polysaccharide or its derivative or make it into beads.

The particle size varies depending on the size of the column and plate used, but is 1-10+wm, preferably 1-3wm.
00-, and the particles are preferably porous.

Further, in order to improve the pressure resistance of the adsorbent, prevent swelling and shrinkage due to solvent substitution, and increase the number of theoretical plates, it is preferable that the polysaccharide or its derivative be retained on a carrier. The appropriate size of the carrier varies depending on the size of the column and plate used, but it is 1 to 1 Ofl111 for -C, preferably 1 x to 300 utm. The carrier is preferably porous, with an average pore size of 10 to 100 nm, preferably 50 to 10,000. The amount of polysaccharide or its derivative retained is 1 to 100% by weight, preferably 5 to 50% by weight, based on the carrier.

The method for retaining the polysaccharide or its derivative on the carrier may be either a chemical method or a physical method. Physical methods include dissolving the polysaccharide or its derivative in a soluble solvent, mixing well with the carrier, and distilling off the solvent with air flow under reduced pressure or heating, or dissolving the polysaccharide or its derivative in a soluble solvent. There is also a method of dispersing the solvent by stirring and dispersing it in a liquid that is incompatible with the solvent after thoroughly mixing it with a carrier.

When crystallizing the polysaccharide or its derivative held on the carrier in this way, a treatment such as heat treatment can be performed. Furthermore, by adding a small amount of solvent to once swell or dissolve the polysaccharide or its derivative, and then distilling off the solvent again, it is possible to change the retention state and, ultimately, the separation ability.

The carrier may be a porous organic carrier or a porous inorganic carrier, preferably a porous inorganic carrier. Suitable porous organic carriers are polymeric materials such as polystyrene, polyacrylamide, polyacrylate, and the like. Also suitable as porous inorganic carriers are synthetic or natural substances such as silica, alumina, magnesia, titanium oxide, glass, silicates, and kaolin, which can be used to improve compatibility with polysaccharides or derivatives thereof. Surface treatment may also be performed. Examples of surface treatment methods include silanization using an organic silane compound and surface treatment using plasma polymerization.

When using polysaccharides or their derivatives for optical resolution, the separation characteristics may change depending on their physical states such as molecular weight, molecular weight distribution, crystallinity, and orientation, even if they are chemically the same derivatives. After or during the process of giving the shape suitable for the intended use, heat treatment,
Etching and other physical and chemical treatments can be applied. In addition, when raw material polysaccharides are often made into derivatives through heterogeneous reactions, the higher-order structure of the raw materials is preserved as is or in part, and even if they are chemically identical to those synthesized through homogeneous reactions, they can be made into derivatives. May have separation properties.

There are no particular restrictions on the developing solvent for liquid chromatography or thin layer chromatography, except for a liquid that dissolves or reacts with the adsorbent. When the adsorbent is bonded to a carrier by a chemical method or made insolubilized by crosslinking, there are no restrictions except for the reactive liquid. Needless to say, the separation characteristics of compounds or optical isomers change depending on the developing solvent, so it is desirable to consider various developing solvents.

In addition, when performing thin layer chromatography, 0.1-~
0.1ml-100I consisting of the adsorbent of the present invention consisting of particles of about 0.1mm and a small amount of binder if necessary
A layer having a thickness of II11 may be formed on the support plate.

[For production]

It is not clear why the polysaccharide-based adsorbent used in the present invention is effective for the optical resolution of lignans. It is not hard to imagine that the less flexible skeleton and two aromatic rings of the lignans having a cyclic structure in the present invention facilitate the identification of asymmetric structures. However, especially in the case of adsorbents whose main components are polysaccharide esters, interaction with the polar groups of the target substance is thought to play an important role, and the separation of lignans with ether bonds or lactone rings is be able to explain that they are effective.

〔Effect of the invention〕

The polysaccharide adsorbent used in the present invention has characteristics suitable for industrial use, such as its raw materials being inexpensive and available in large quantities, and being chemically stable. Therefore, by using the method of the present invention, it has become possible to utilize racemic or lignans with low optical purity as optically active substances.

〔Example〕

EXAMPLES The present invention will be specifically explained below with reference to Examples, but it goes without saying that the present invention is not limited to these Examples.

Example 1 A mixture of enantiomers of syringaresinol (1) was optically resolved by liquid chromatography using a packing material made of silica gel supporting cellulose triphenyl carbamate.

The chromatogram is shown in FIG.

The liquid chromatography column used was a stainless steel column with a length of 25 CI11 and an inner diameter of 0.46 cm, which was filled with a packing material in which about 22% by weight of cellulose trisphenyl carbamate was supported on silica gel treated with diphenylsilane. .

The liquid chromatography conditions were as follows: 1 ml of ethanol was pumped per minute as an eluent, and the column temperature was maintained at 40°C. An ultraviolet detector was used for detection.

[Brief explanation of drawings]

FIG. 1 is a chromatogram showing the results of optical resolution in Example 1.

Claims (1)

[Claims] A method for optically resolving lignans, which comprises optically resolving a mixture of optical isomers of lignans by chromatography using an adsorbent containing a polysaccharide derivative as an active ingredient.