JPS61225138A - Optical resolution of alcohol bearing atomic groups containing multiple bonds - Google Patents

Abstract

PURPOSE:An enatiomer mixture of asymmetric alcohol or its derivative bearing groups containing multiple bonds other than aryl and heteroaryl groups is optically resolved by means of a separating agent containg a polysaccharide derivative as an active component. CONSTITUTION:Optical resolution of an enantiomer mixture of asymmetric alcohol such as a compound of formula I, II, III or IV bearing atomic groups containing multiple bonds other than aryl and heteroaryl groups or its derivative is effected by means of a resolution agent which is composed of a polysaccharide or its derivative. Homoglycan of high regularity is preferred as a resolution agent and cellulose, amylose and beta-1,4-chitosan which are readily available in a pure form is more preferred. The resolution agent is used as such or immobilized on a carrier and used in a column for liquid or gas chromatography.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method for optical resolution of alcohols having atomic groups containing multiple bonds in their molecules.

[Conventional technology and problems]

Optical isomers of asymmetric compounds usually have different physiological actions, and therefore, in the field of medicine and agrochemicals, using only one enantiomer can eliminate side effects or increase the medicinal efficacy per dose. It may lead to

Recently, the use of asymmetric compounds in optical materials such as liquid crystals has also been considered. Due to these circumstances, compounds that have or can have such uses have recently been
Alternatively, optically active forms of compounds that can be synthetically used as raw materials are in great demand as industrial raw materials and research reagents. A group of compounds targeted by the optical resolution method of the present invention have two functional groups in the molecule: a hydroxyl group and an atomic group containing a multiple bond, and both have an extremely wide range of synthetic applications. Therefore, it is of great significance to establish a method for obtaining these optically active forms that can be easily industrialized.

Conventional methods for obtaining optically active substances include asymmetric synthesis, optical resolution after induction into diastereomers, and biochemical methods using enzymes or microorganisms.

These medium asymmetric synthesis methods have the problem of not being able to obtain the target compound with high optical purity. The stereomer method has a problem in that equimolar amounts of different optically active compounds are required. Another disadvantage of biochemical methods is that it is difficult to find suitable enzymes and microorganisms.

[Means for solving problems]

In view of the shortcomings of conventional asymmetric synthesis methods and optical resolution methods as described in the previous section, the present inventors have developed an optically active compound that has many advantages such as being simple, applicable for multiple purposes, and easy to industrialize. As a result of investigating methods for obtaining these compounds, it was discovered that a separation method using adsorption or diffusion using a separation agent containing a polysaccharide derivative as an active ingredient can be effectively applied to these compounds.

That is, the present invention is characterized in that an enantiomeric mixture of an asymmetric alcohol or a derivative thereof having an atomic group containing multiple bonds other than an aryl group or a heteroaryl group is optically resolved using a separation agent containing a polysaccharide derivative as an active ingredient. This invention provides a method for optical resolution of alcohols having atomic groups containing multiple bonds.

Suitable dihydric alcohols to be subjected to optical resolution in the present invention have carbon atoms of 10 or less, contain a skeleton of the following formula, and are asymmetric.

+1O-C-(C) n-X (I) where,
All hydrogen atoms, side chains, substituents, etc. are omitted, but
In order for the alcohol to be asymmetric, in addition to a hydrogen atom and etc.) OR2, 5R2 (R2 is a group selected from II and R1)
■ Contains one or more atoms or atomic groups such as (halogen atom). If an even number of these atoms or atomic groups is included, they must be included in positions where the molecule is asymmetric.

Further, in the formula, n is O, L 2.3.4.5, and preferably sails 1 and 2.

X is selected from the following atomic groups containing multiple bonds.

-CI(-CIlR2 -c=cR2 -C=N O(Y is R2, OR2, N11z3NIIR', N
R'2゜-C-'lSR'') c-y No2 NC In the formula, R1 and R2 are the same as in the formula (1), and the same applies below.

Specific examples include the following.

Allyl alcohol, homoallyl alcohol and corresponding acetylenic compounds such as. These compounds are important as synthetic precursors because they can undergo various chemical transformations such as hydrogenation of unsaturated bonds, oxidation, cleavage, and stereoselective addition (especially epoxidation). For example, optically active 4-pentene-2
There is an example of synthesizing prostanoids using -ol (
C, T, Sih, Prostaglandins (
1977) 831).

α- or β-hydroxycarbonyl compounds such as +1. These skeletons often appear in natural physiologically active substances. In particular, β-hydroxyketones or aldehydes are easily obtained by aldol condensation type reactions and are essential intermediates in various organic syntheses.

Human'roxynitrile such as. The α-form can be easily obtained by adding HCN to aldehyde, and the β-form can be easily obtained by reacting epoxide with CN-.
It is an important intermediate because it can be converted into various functional groups such as R'', CIhNII□, etc.

(4) No.

vicinal hydrogycinitro compounds such as R2 may be different. These compounds are easily obtained by a condensation reaction between a nitroalkane and an aldehyde, and because the nitro group can be converted into an amino group by reduction, they have recently attracted attention as synthetic intermediates.

Vicinal hydroxyazides such as (51N3) can be obtained by reaction of epoxide and azide ion, and the azide group can be easily converted to an amino group.

Hydroxysulfones such as CH3 can be easily obtained by reacting epoxide and thiolate ion, and then adding an oxidized α-sulfonyl carbanion to a carbonyl compound, and further substituting the sulfur atom with hydrogen or other atomic group. It is a highly useful intermediate.

When optically resolving an alcohol, which is the object of the present invention, the alcohol is often converted into an ester or ether with an achiral atomic group such as acetate, benzoate, cinnamate, benzenesulfonate, toluenesulfonate, methanesulfonate, benzyl ether, etc. Division may be possible by conversion. Most of these derivatives can be removed by reaction with nucleophiles, hydrogenation, etc., but they can be removed by substitution, such as sulfonic acid esters.
Some can be used directly for next step reactions such as elimination.

Whether it is better to directly resolve a certain alcohol or to chemically modify it depends on the case - although it is not possible to generalize, the polysaccharide separating agent used in the present invention often effectively resolves the alcohol itself. .

The separating agent used in the present invention contains polysaccharides and derivatives thereof as active ingredients. The polysaccharide referred to here may be a synthetic polysaccharide, a natural polysaccharide, or a modified natural polysaccharide, as long as it is optically active, but it is preferably a homoglycan with a high degree of regularity and a fixed bonding pattern. It is something that is. More preferred are cellulose, amylose, β-1,4-chitosan, chitin, β-1,4-mannan, β-1,4-xylan, inulin, and α-1°, from which highly pure polysaccharides can be easily obtained. 3-glucan, β-1,3
-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. The atomic group referred to herein is a cycloaliphatic group consisting of 3 to 8 carbon atoms, an aromatic group or a heteroaromatic group consisting of 4 to 20 carbon atoms, and any of them may have a substituent. These derivatives 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.

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

Methods for producing the separating agent in the present invention include the following.

In order to use it as a liquid chromatography method or a gas chromatography method, the polysaccharide or its derivative can be used by filling a column as it is, by holding it on a carrier and packing it, or by coating it on a capillary column.

Since the separating agent for chromatography is preferably in the form of particles, in order to use the polysaccharide or its derivative as a separating agent for compounds, it is preferable to crush the polysaccharide or its derivative or make it into pieces.

The size of the particles varies depending on the size of the column or plate used, but is 1 μm to 10 mm, preferably 1 μm to 10 mm.
Preferably, the particles are porous, between .mu.m and 300 .mu.m.

Further, in order to improve the pressure resistance of the separating agent, to prevent swelling and shrinkage due to solvent substitution, and to improve the number of theoretical plates, it is preferable to hold the polysaccharide or its derivative on a carrier. The appropriate size of the carrier varies depending on the size of the column and plate used, but is generally 1 μm to 10 mm, preferably 1 μm to 300 μm. The carrier is preferably porous, with an average pore size of 10 to 100 μm,
Preferably 50 to 10,000 people. 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 include polymeric substances such as polystyrene, polyacrylamide, and polyacrylate. Suitable porous inorganic carriers include synthetic or natural substances such as silica, alumina, magnesia, titanium oxide, glass, silicates, and kaolin, which may be surface-treated to improve their affinity with the polysaccharide or its derivatives. You may do so. 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. , heat treatment after or during the process of giving the shape suitable for the intended use,
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 result in separation properties.

When used in liquid chromatography, solvents that do not dissolve the polysaccharide or its derivative cannot be used as a developing solvent, but when the polysaccharide or its derivative is bonded to a carrier by a chemical method,
There are no particular restrictions when the polysaccharide or its derivative is crosslinked.

In addition, when performing thin layer chromatography, 0.1 μ
0.1 mm to 100 particles consisting of the separating agent of the present invention consisting of particles of about 0.1 mm to 0.1 mm and a small amount of a binder if necessary
A layer with a thickness of mm may be formed on the support plate.

Examples of means for obtaining the optically active substance of the present invention using the separating agent described in 1. include chromatography methods such as gas chromatography, liquid chromatography, and thin layer chromatography.

The developing solvent used in liquid chromatography or thin layer chromatography is not particularly limited, except for a liquid that dissolves or reacts with the separating agent. When the separation agent 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.

[Effect]

It is not clear why the polysaccharide separating agent of the present invention is effective in the optical resolution of the alcohols and their derivatives. However, considering that it is extremely difficult to optically resolve simple alcohols or their ester derivatives that have no other functional groups, it is important to note that the π-π Electronic interactions such as interactions work, and when hydrogen bonding interactions of alcoholic hydroxyl groups or interactions of ester and ether moieties of its derivatives are added to this, there are multiple interaction points in total, and the It is expected that effective asymmetric identification will be achieved as a result.

〔Effect of the invention〕

The separating agent used in this process has characteristics suitable for industrial use, such as raw materials that can be obtained in large quantities at low cost and chemical stability. It is well known to some extent that aromatic compounds are often effectively separated by these separation agents, and aromatic and heteroaromatic compounds that lack any conformational freedom and have considerable size. It is no wonder that compounds containing group groups are more easily recognized for their asymmetric structure. However, until now, there have been no examples of splitting alcohols that do not contain aromatic groups, except for very limited cyclic compounds, and a wide range of compounds including acyclic compounds that fall under the present invention have been split. That is surprising.

As described above, although its mechanism of action is not completely clear, the method of the present invention has been shown to eliminate numerous optical isomers by optical resolution of racemates or by removal of unnecessary optical isomers generated during incomplete asymmetric synthesis. It is clear that useful optically active compounds can be easily obtained. The present invention provides a completely new source of optically active raw materials in the field of optically active compound synthesis, which has traditionally been carried out using a variety of limited natural compounds as starting materials.

〔Example〕

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

The liquid chromatography column used was a stainless steel column with a length of 25c+n and an inner diameter of 0.46cm, which was filled with a packing material in which about 2% by weight of a cellulose derivative was supported on diphenylsilane.

The liquid chromatography conditions were as follows: 0.5 ml of hexane-2-propatol (9:l) was pumped per minute as an eluent, and the column temperature was maintained at 20°C±2°C. For detection, use an ultraviolet detector (Shimadzu 5PD-■ or Hitachi 635M)
) and/or differential refractometer (Elma Optics EllC75
10) was used.

The table below shows the compounds to be resolved, the division coefficient (α) between their respective optical isomers, and the active ingredients of the separating agent. The resolution coefficient (α) is defined as the retention capacity of a strongly retained optical isomer - the dead volume of the column - the retention capacity of a weakly retained optical isomer - the dead volume of the column, and serves as an index of the quality of the resolution.

Table: Optical resolution of alcohols or their derivatives with atomic groups containing multiple bonds

Claims (1)

[Claims] An atom containing multiple bonds, characterized in that an enantiomeric mixture of an asymmetric alcohol or its derivative having an atomic group containing multiple bonds other than an aryl group or a heteroaryl group is optically resolved using a separation agent containing a polysaccharide derivative as an active ingredient. Optical resolution method for alcohols with groups.