JPS61176558A - Method of optical presolution of nitrile - Google Patents

Abstract

PURPOSE:To obtain various enantiomers, by subjecting a nitrile to optical resolution by the use of a resolving agent comprising an optically active natural polysaccharide derivative as an active ingredient. CONSTITUTION:A nitrile shown by the formula (Ar is aromatic or heterocyclic; R is alkyl, substituted alkyl or alkoxy) is subjected to optical resolution by the use of a separating agent (e.g., homoglycan having high regularity, such as preferably cellulose, amylose, or alpha-1,3-glycan) comprising a polysaccharide or its derivative as an active ingredient by chromatography. EFFECT:An optically active nitrile useful as an intermediate for important asymmetric synthesis is made easily obtainable by simple chromatographic technique without converting chemically an inexpensive raw material.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a method for obtaining each enantiomer of a nitrile represented by the following general formula (1) by optical resolution.

Ar -C-CN (1) (Ar is an aromatic group or a heteroaromatic group, R is an alkyl group, a substituted alkyl group, or an alkoxy group) [Prior art and its problems] Each enantiomer of an asymmetric compound They often have different effects on living organisms, and for this reason optical resolution and asymmetric synthesis methods are one of the biggest challenges in current organic chemistry.

Now, the nitriles represented by the above general formula (1) are highly useful as intermediates in the synthesis of organic compounds, such as giving corresponding carboxylic acids when hydrolyzed and ketones when reacting with Grignard reagents. One of the compounds that can be derived from this is arylpropionic acid derivatives, which are attracting attention as anti-inflammatory agents. Therefore, if an optically active form of the compound represented by the above general formula (1) can be provided, it will make a significant contribution to the field. However, in general, nitriles are chemically inert and it is not possible to obtain a reversible diastereomeric link reaction product with other optically active compounds. It has been common practice to perform optical resolution or to use optically active substances of natural origin as synthetic raw materials. Therefore, it would be of great significance if the compound represented by the general formula (1) could be optically resolved directly by an industrially easy method.

[Means for solving problems]

As a result of extensive studies, the present inventors have found that a separation agent containing an optically active natural polysaccharide derivative as an active ingredient has the following general formula (1):
The present inventors have discovered that the present invention is extremely effective in the optical resolution of compounds represented by the following formulas, and have completed a method for isolating each enantiomer of these compounds using this method, leading to the present invention.

That is, the present invention provides a compound represented by the general formula % (1) (Ar is an aromatic group or a heteroaromatic group, R is an alkyl group, a substituted alkyl group, or an alkoxy group) using a polysaccharide derivative as an active ingredient. The present invention relates to a method for optically resolving nitriles, which is characterized by optically resolving using a separating agent.

In the present invention, the compound to be optically resolved is represented by the general formula (1) above, and Ar is an aromatic group or a heteroaromatic group, such as phenyl, α-
These include naphthyl, β-naphthyl, pyridyl, quinolinyl, or substituted derivative groups thereof. R is an alkyl group, an alkyl group having a substituent, or an alkoxy group,
Preferable examples include methyl group, ethyl group, propyl group, butyl group, isopropyl group, cyclopropyl group, cyclohexyl group, cyclopentyl group, methoxy group, and ethoxy group.

The separating agent used in the present invention contains polysaccharides and derivatives thereof as active ingredients. The polysaccharide referred to here may be any optically active polysaccharide, including synthetic polysaccharides, natural polysaccharides, and modified natural polysaccharides, but it is preferably a highly regular homoglycan with a constant bonding pattern. It is something. More preferably, cellulose, amylose, β-1,4-chitosan, chitin, β-1,4-mannan, β-1,4-
xylan, inulin, α-1゜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 here is an aliphatic group having 1 to 3 carbon atoms, a cycloaliphatic group having 3 to 8 carbon atoms, an aromatic group or a heteroaromatic group having 4 to 20 carbon atoms. These derivatives, which may each 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.

In the optical resolution method of the present invention, the desired nitriles 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 separation agent for chromatography is preferably in the form of particles, in order to use the polysaccharide or its derivative as a separation agent for compounds, it is preferable to crush the polysaccharide or its derivative or form it into beads.

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

Furthermore, the pressure resistance of the separation agent is improved, swelling due to solvent replacement,
In order to prevent shrinkage and improve the number of theoretical plates, the polysaccharide or its derivative is preferably retained on a carrier. The appropriate size of the carrier varies depending on the size of the column or plate used, but is generally 1 μm + 1 to 10 mm, preferably 1 μm to 300 μm. The carrier is preferably porous, with an average pore diameter of 10 to 100 μm, preferably 50 to 10,000 μm. The amount of polysaccharide or its derivative retained is 1 to 100% by weight based on the carrier;
Preferably it is 5 to 50% by weight.

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, crystallinity, and orientation, even if the derivatives are chemically the same. Heat treatment, etching, and other physical or chemical treatments can be applied after or during the process of imparting a shape suitable for use.

Solvents that dissolve polysaccharides or their derivatives cannot be used as developing solvents when used in liquid chromatography, but when polysaccharides or their derivatives are 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
0,11III-1 consisting of the separating agent of the present invention consisting of particles of about m to 0.1 mm and, if necessary, a small amount of a binder.
A layer with a thickness of 0.00 mm may be formed on the support plate.

As means for obtaining the optically active substance of the present invention using the above-mentioned separating agent, there are chromatography methods such as gas chromatography, liquid chromatography, and thin layer chromatography.

When performing liquid chromatography or thin layer chromatography, there are no particular restrictions on the developing solvent, except for liquids that dissolve or react with the separating agent. When insolubilized by crosslinking, there are no restrictions except for reactive liquids. 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]

The reason why the method of the present invention effectively achieves optical resolution of the compound represented by the general formula (1) is not clear, but the reason is that the corresponding aldehyde or carboxylic acid ester is not effectively optically resolved with nitrile. Therefore, it is thought that the cylindrical structure of the nitrile group with good symmetry or the structure with small steric bulk that easily causes electron orbital interaction is largely involved in the interaction with the separating agent.

〔Effect of the invention〕

As described above, the present invention facilitates the acquisition of optically active nitriles, which are important intermediates for asymmetric synthesis, by using a simple chromatography technique without any chemical conversion of inexpensive raw materials. It is something.

〔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.

In the examples, the liquid chromatography column used was a porous silica gel LichrosperSilO obtained by treating a suitable cellulose derivative with diphenylsilane.
A filler with a weight of about 22% carried on 00 was 25 cm long,
A stainless steel column with an inner diameter of 0.46 cm was used.

In addition, the eluting optical isomer was detected using an ultraviolet detector (Shimadzu 5
PD-If), differential refractometer (Showa Denko 5hodex R
I5E31) and a polarimeter equipped with a flow cell (JASCO Corporation DIP181).

Example I A chromatogram obtained by optical resolution of C&H8CHCH3CN (purchased from Aldrich and purified by liquid chromatography using silica gel) is shown in FIG. The stationary phase was cellulose tribenzoate, and the eluent was hexane-2-propanol (9:1).
, the flow rate was Q, 5 m/win, the analysis temperature was 20° C., and ultraviolet absorption at 210 na+ was used for detection.

Example 2 FIG. 2 shows a chromatogram obtained by optically resolving CJsCHCHsCN under the same conditions as in Example 1 using cellulose triacetate as the stationary phase.

Example 3 FIG. 3 shows a chromatogram obtained by optically resolving CJsCHCHsCN under the same conditions as in Example 1 using cellulose tricinnamate as the stationary phase.

[Brief explanation of drawings]

Figures 1.2 and 3 are chromatograms of CJsCHCH2CN optically resolved in Examples 1, 2 and 3, respectively.

Claims (1)

[Claims] A compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (1) (Ar is an aromatic group or a heteroaromatic group, R is an alkyl group, a substituted alkyl group, or an alkoxy group) , a method for optical resolution of nitriles, characterized by optical resolution using a separation agent containing a polysaccharide derivative as an active ingredient.