JP2517639B2 - Method for optical resolution of α-hydroxy acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The present invention provides an optical resolution of an α-hydroxy acid derivative such as a 2-hydroxy-4-phenylbutyric acid derivative.
The present invention relates to an optical resolution method for obtaining each enantiomer.

The optically resolved α-hydroxy acid derivative can be used as it is for its physiological activity, but it is also used as an intermediate in organic synthesis to obtain various optically active compounds. Optical isomers of compounds having asymmetry usually have different physiological actions, which is the main reason why optically active compounds are required. The optically active compounds thus obtained are used as medical and agricultural chemicals, and have various demands as optical materials such as liquid crystals and reagents for research. For example, (R) -2-hydroxy-4-
Phenylbutyric acid derivatives are demanding intermediates for various pharmaceuticals and optically active physiologically active substances such as enalapril and its derivatives.

[Problems to be Solved by Prior Art and Invention]

Each enantiomer of an asymmetric compound often has a different action on the living body as described above. Therefore, the method of optical resolution and asymmetric synthesis is one of the biggest problems in the current organic chemistry. There is.

Conventional methods for obtaining optically active compounds include asymmetric synthesis, optical resolution after diastereomeric induction, and biochemical methods using enzymes and microorganisms. The asymmetric synthesis method has a problem that a compound having a high optical purity of a target compound cannot be obtained, and a method of obtaining a diastereomer cannot easily form a diastereomer derivative,
The diastereomer method has a problem in that equimolar different kinds of optically active compounds are required. Further, the biochemical method has a drawback that it is difficult to find an appropriate enzyme or microorganism.

The situation is the same for the 2-hydroxy-4-phenylbutyric acid derivative, which is a typical compound of the α-hydroxy acid derivative targeted by the present invention, and in particular, the corresponding carbonyl compound is obtained by asymmetric hydrogenation. There is an attempt (Eur.Pat.EP206993), but the optical yield is still unsatisfactory.

Since α-hydroxy acid derivatives such as 2-hydroxy-4-phenylbutyric acid derivatives are very useful substances, they can be used as they are, or if they can be separated by a chromatographic method after a simple chemical conversion, they can be used as chromatographs. As long as the stationary phase for chromatography is sufficiently stable and inexpensive, it can be easily industrialized and its contribution is extremely large.

[Means for solving the problem]

The present inventors have conducted extensive studies to solve the above-mentioned problems, and as a result, a separating agent containing an optically active cellulose derivative as an active ingredient directly converts this α-hydroxy acid derivative into an ester derivative or an aralkyl derivative. The present invention has been completed by finding that even in such a case, a remarkable effect is exerted on the optical resolution.

That is, the present invention has the general formula (I) (In the formula, X ₁ and X ₂ are each a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group or an alkyl group, and R is a hydrogen atom, an alkyl group or a phenyl group, and n = 1 to 3). The enantiomer mixture of the α-hydroxy acid derivative shown above is directly used, or after the α-position hydroxyl group is modified with an optically inactive acyl group, aralkyl group, aryl group or sulfonyl group, one of the hydrogen atoms on the hydroxyl group of cellulose is Part or all (In the formula, R ¹ is an aromatic group having 4 to 20 carbon atoms.) A cellulose derivative substituted with a group represented by the formula ( ¹ ) is optically resolved by a separating agent containing an active ingredient α -It relates to a method of optical resolution of a hydroxy acid derivative.

The α-represented by the general formula (I) used in the present invention
In the hydroxy acid derivative, the alkyl group represented by X ₁ and X ₂ R preferably has 1 to 4 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a propyl group and an isopropyl group. A typical example of the α-hydroxy acid derivative used in the present invention is a 2-hydroxy-4-phenylbutyric acid derivative represented by the following general formula (II).

(In the formula, R means the same groups as described above) The optical resolution of the α-hydroxy acid derivative according to the present invention is
The hydroxyl group at the α-position is used as it is, or the hydroxyl group at the α-position is modified with an acyl group, an aralkyl group, an aryl group or a sulfonyl group. The modification here specifically means substitution of a hydrogen atom in the hydroxyl group at the α-position of the α-hydroxy acid derivative with an atomic group selected from the group shown below.

HCO, CH ₃ (CH ₂ ) _m CO (m = 0,1,2,3,4,5,6,7,8) (CH ₃ ) ₂ CHCO, (CH ₃ ) ₃ CCO, Cl ₃ CCO, The α-hydroxy acid derivative optically resolved by the method of the present invention may be directly subjected to the following chemical conversion, but α-
When it is desired to regenerate the hydroxy acid derivative, the ester derivative may be decomposed with water or alcohol in the presence of acid or alkali, and the ether derivative may be catalytically reduced.

The separating agent containing a cellulose derivative as an active ingredient, which is used in the present invention, is rich in raw materials, and can be prepared relatively easily from the raw materials. It also has excellent chemical stability and has properties suitable for industrial chromatographic separation.

The cellulose derivative in the present invention is part or all of hydrogen atoms on the hydroxyl group of cellulose, preferably
85% or more are substituted with the above atomic groups. These derivatives can be easily obtained by using various known chemical reactions. These cellulose derivatives are particularly suitable for industrial chromatographic separation because of the availability of raw materials and the stability.

In the optical resolution method of the present invention, by selecting an appropriate one from these cellulose derivatives as a separating agent,
Optical resolution of the desired α-hydroxy acid derivative can be performed.

In the present invention, as means for optically resolving an α-hydroxy acid derivative using a separating agent containing the above cellulose derivative as an active ingredient, a gas chromatography method, a liquid chromatography method, a thin layer chromatography method, or the like can be used. A chromatographic method can be mentioned.

In order to use the separating agent according to the present invention as a liquid chromatography method or a gas chromatography method, the cellulose derivative may be packed in a column as it is, packed on a carrier while being packed, or coated on a capillary column.

Since the chromatographic separating agent is preferably granular, in order to use the cellulose derivative as the separating agent, the cellulose derivative is crushed, but preferably in the form of beads. The size of the particles varies depending on the size of the column or plate used, but is preferably 1 μm to 10 mm, more preferably 1 μm to 300 μm, and the particles are preferably porous.

Further, in order to improve the pressure resistance of the separating agent, prevent swelling and contraction due to solvent substitution, and improve the theoretical plate number, it is preferable to hold the cellulose derivative on a carrier. The size of a suitable carrier varies depending on the size of the column or plate used, but is generally 1 μm to 10 mm, preferably 1 μm.
m to 300 μm. The carrier is preferably porous, and the average pore diameter is preferably 10Å to 100 µm, more preferably 50Å to 10000Å. The amount of the cellulose derivative retained is 1 to 100% by weight, preferably 5 to 5% with respect to the carrier.
It is 0% by weight.

The method of holding the cellulose derivative on the carrier may be a chemical method or a physical method. As a physical method, a cellulose derivative is dissolved in a soluble solvent, well mixed with a carrier, a method of distilling off the solvent by an air stream under reduced pressure or heating, or a cellulose derivative is dissolved in a soluble solvent to form a carrier. After mixing well, there is also a method in which the solvent is dispersed by stirring and dispersing it in a liquid that is incompatible with the solvent. When crystallizing the cellulose derivative held on the carrier in this way, a treatment such as heat treatment can be performed. Further, by adding a small amount of solvent to swell or dissolve the cellulose derivative and then distilling off the solvent again, it is possible to change the retention state, and thus the separability.

The carrier used in the present invention may be a porous organic carrier or a porous inorganic carrier, preferably a porous inorganic carrier. Suitable examples of the porous organic carrier 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 are surface treated to improve their affinity with cellulose derivatives. You can go. Examples of the surface treatment method include a silanization treatment using an organic silane compound and a surface treatment method by plasma polymerization.

When a cellulose derivative is used for optical resolution, the separation characteristics may change depending on the physical state such as molecular weight, crystallinity, orientation, etc. even if the derivatives are chemically the same, so the intended use After or in the process of giving a suitable shape, a heat treatment, etching or other physical or chemical treatment can be applied.
In addition, the cellulose derivative synthesized by the heterogeneous reaction often retains the higher-order structure of the raw material cellulose and has a different higher-order structure even though it is chemically identical to that synthesized by the homogeneous reaction. May result in improved separation characteristics.

In the present invention, as a developing solvent when performing liquid chromatography or thin layer chromatography,
There is no particular limitation except the liquid that dissolves or reacts with the cellulose derivative. When the cellulose derivative is bound to the carrier by a chemical method or is insolubilized by crosslinking, there is no limitation except for the reactive liquid. Needless to say, since the separation characteristics of the α-hydroxy acid derivative vary depending on the developing solvent, it is desirable to study various developing solvents.

When performing thin layer chromatography, 0.1 μm
A layer having a thickness of 0.1 mm to 100 mm consisting of the separating agent of the present invention composed of particles of about 0.1 mm and a small amount of a binder, if necessary, may be formed on the support plate.

[Work]

Although the reason why the optical resolution of the α-hydroxy acid derivative is effectively achieved by the method of the present invention is not clear, the aromatic ring or the ester group effectively interacts with the cellulose derivative, and the chirality of the cellulose derivative is improved. It is considered that this reflects and brings about good optical resolution.

〔The invention's effect〕

The present invention is as described above, and established a method for obtaining an optically active α-hydroxy acid derivative useful as a drug or a synthetic intermediate from a racemic raw material by a simple chromatography technique.

〔Example〕

Hereinafter, the present invention will be specifically described with reference to Examples.
It goes without saying that the present invention is not limited to these.

The parameters k'and α used in the embodiment are defined as follows.

Example 1 2-Hydroxy-4-phenylbutyric acid ethyl ester racemate was treated with silica gel obtained by treating cellulose tribenzoate with diphenylsilane (Lichrospher Si manufactured by Merck).
1000) with a separating agent loaded so as to be about 22% by weight, two stainless steel columns with an inner diameter of 4.6 mmφ and a length of 25 cm are connected and used as a column for liquid chromatography. Eluent: hexane / 2- Propanol (39: 1), temperature
Optical resolution was performed under the conditions of 40 ° C. and a flow rate of 0.5 ml / min. The chromatogram at this time is shown in FIG.

Ultraviolet detector (Shimadzu SPD-I
I), using UV absorption at a wavelength of 254 nm. The determination of the (R) form and the (S) form was carried out by fractionating, purifying by a usual method, and measuring the degree of light application.

The volume ratio and the separation coefficient of the (R) form and the (S) form were as follows.

k ₁ ′ = 2.03 k ₂ ′ = 2.56 α = 1.26 Example 2 Acetoxylated 2-acetoxy-4-hydroxyl group of 2-hydroxy-4-phenylbutyric acid ethyl ester
The racemic form of phenylbutyric acid ethyl ester was optically resolved using the same column as in Example 1 under the conditions of eluent: hexane / 2-propanol (9: 1), temperature: 20 ° C, flow rate: 0.5 ml / min. . The chromatogram at this time is shown in FIG.

Ultraviolet detector (Shimadzu SPD-I
I), using UV absorption at a wavelength of 254 nm. The determination of the (R) form and the (S) form was carried out by fractionating, purifying by the usual method, and measuring the degree of light application.

The volume ratio and the separation coefficient of the (R) form and the (S) form were as follows.

k ₁ ′ ＝ 3.06 k ₂ ＝＝ 4.61 α ＝ 1.51

[Brief description of drawings]

FIG. 1 and FIG. 2 are diagrams showing split chromatograms obtained in Examples 1 and 2, respectively.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location C07C 67/60 C07C 67/60 69/732 9546-4H 69/732 Z 201/16 201/16 205 / 56 205/56 // C07B 57/00 346 C07B 57/00 346

Claims (2)

(57) [Claims] 1. A general formula (I) (In the formula, X ₁ and X ₂ are each a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group or an alkyl group, R is a hydrogen atom, an alkyl group or a phenyl group, and n is a number of 1 to _3. )
In the enantiomeric mixture of α-hydroxy acid derivative represented by directly or after modifying the α-position hydroxyl group with an optically inactive acyl group, aralkyl group, aryl group or sulfonyl group, the hydrogen atom on the hydroxyl group of cellulose is Some or all (In the formula, R ¹ is an aromatic group having 4 to 20 carbon atoms.) A cellulose derivative substituted with a group represented by the formula ( ¹ ) is optically resolved by a separating agent containing an active ingredient α -Optical resolution method of hydroxy acid derivative. 2. The optical resolution method according to claim 1, wherein the α-hydroxy acid derivative is a 2-hydroxy-4-phenylbutyric acid derivative.