JPH0273045A - Optical resolution of amine derivative - Google Patents

Abstract

PURPOSE:To efficiently optically resolve the enantiomer mixture of an amine acyl derivative with a separating agent containing a polysaccharide or a derivative thereof as an effective component. CONSTITUTION:The enantiomer mixture of an amine acyl derivative of the formula (X1 and X2 are H, halogen, OH, nitro or alkyl; COR is acyl; n is 1-3) is optically resolved by a chromatography method using a separating agent containing a polysaccharide (e.g. cellulose) or a derivative thereof as an effective component. The optically resolved optically active isomer of the amine acyl derivative is useful as a synthetic intermediate for various medicines and agricultural chemicals. The amine acyl derivative is N-acetyl-2-amino-4-phenylbutane.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a method for optical resolution of amine derivatives. More specifically, - maximum (1) (where xl and x2 are each a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, or an alkyl group, COR is an acyl group, and n is an integer of 1 to 3.) The present invention relates to an optical resolution method for obtaining each enantiomer by optically resolving an enantiomeric mixture of an acyl derivative of an amine. Optically active forms of optically resolved acyl derivatives of amines are useful as synthetic intermediates for various pharmaceuticals and agricultural chemicals.

(Problems to be solved by conventional techniques and inventions) Conventionally,
Methods for obtaining optically active forms include asymmetric synthesis, optical resolution after induction into diastereomers, and biochemical methods using enzymes or microorganisms.

The asymmetric synthesis method has the problem that it is not possible to obtain a compound with high optical purity of the target compound. However, there was a problem in that equimolar amounts of different types of optically active compounds were required. Biochemical methods have the disadvantage that suitable enzymes and microorganisms are difficult to find.

The situation is the same in the case of acyl derivatives of amines, which are the object of the present invention, and it would be extremely useful if excellent optical resolution means could be developed.

- The optically active form of the acyl derivative of amine represented by maximum (1) is a very useful compound, so if it can be optically resolved by chromatography as it is or after a simple chemical conversion, it can be used. As long as a stationary phase for chromatography that can be used is sufficiently stable and inexpensive, industrialization will be easy, and its contribution will be extremely large.

[Means to solve the problem]

The present inventors have solved the above-mentioned problem (as a result of extensive studies, we have found that a separation agent containing a polysaccharide or its derivative as an active ingredient can be used to solve the above problem). The present invention was achieved by discovering that this method is extremely effective in partitioning.

That is, the present invention provides - Maximum (1) C In the formula, xl and X are each a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, or an alkyl group, COR is an acyl group, and n is an integer of 1 to 3. The present invention provides a method for optically resolving amine derivatives, which comprises optically resolving an enantiomeric mixture of acyl derivatives of amines represented by (1) using a separating agent containing a polysaccharide or a derivative thereof as an active ingredient.

In the acyl derivative of the amine shown in maximum (1) above used in the present invention, specific examples of the halogen atom represented by the island x2 include CI and Br.

Specific examples of alkyl groups such as F and I include methyl group,
Specific examples of the acyl group represented by COR include an ethyl group, a propyl group, an isopropyl group, a benzyl group, and an acetyl group, a propionyl group, a butyryl group, and the like.

Further, as a specific example of the acyl derivative of the amine represented by the general formula (I) that can be used in the present invention, N-acetyl-2-amino-4-phenylbutane and the like can be mentioned.

The optically active form of the amine acyl derivative optically resolved by the method of the present invention may be directly subjected to the next chemical conversion depending on the use, but in some cases it may be hydrolyzed in the presence of an acid or alkali to form an optically active form. It can also be used as a free amine as various synthetic intermediates.

Furthermore, the separation agent containing a polysaccharide or a derivative thereof as an active ingredient used in the present invention has an abundance of raw materials, and can be prepared relatively easily from the raw materials. It also has excellent chemical stability and has properties suitable for industrial and chromatographic separations.

The polysaccharide used in the present invention may be any optically active polysaccharide, regardless of whether it is a synthetic polysaccharide, a natural polysaccharide, or a modified natural polysaccharide, but the preferred polysaccharide is a highly regular homoglycan. The bonding style is also constant. More preferably used are cellulose, amylose, and β-1, from which highly pure polysaccharides can be easily obtained.
, 4-chitosan, chitin, β-1,4-mannan, β-
1,4-xylan, inulin, α-1,3 glucan, β
-1,3-glucan and the like.

In the present invention, the polysaccharide derivative refers to some or all of the hydrogen atoms on the hydroxyl groups of the polysaccharide, preferably 85
% or more is replaced with other atomic groups. The atomic groups mentioned here include the formula % formula % (wherein R' is an aliphatic group consisting of 1 to 3 carbon atoms, a cycloaliphatic group consisting of 3 to 8 carbon atoms, an aromatic group consisting of 4 to 20 carbon atoms) group or a heteroaromatic group, both of which 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, by selecting an appropriate one from these polysaccharides or derivatives thereof as a separating agent,
Optical resolution of a mixture of enantiomers of an acyl derivative of a target amine can be performed.

In the present invention, methods for optically resolving enantiomeric mixtures of acyl derivatives of amines using a separation agent containing the above polysaccharide or its derivative as an active ingredient include gas chromatography, liquid chromatography, and thin layer chromatography. Examples include chromatography methods such as chromatography methods.

In order to use the separation agent according to the present invention in a liquid chromatography method or a gas chromatography method, the polysaccharide or its derivative may be packed into a column as it is, held on a carrier and packed, or coated onto 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, it is preferable to crush the polysaccharide or its derivative or make it into beads.

Although the size of the particles varies depending on the size of the column or blade used, it is preferably l- to 10n+m, more preferably 1 to 300-m, and the particles are preferably porous.

Further, in order to improve the pressure resistance of the separation agent, 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 is generally 1414-1O+, preferably 1 to 1.
It is 300-. Preferably, the carrier is porous;
The average pore size is preferably 10 to 100 tm, more preferably 50 to 10,000 tm. 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 the carrier.

When crystallizing the polysaccharide or its derivative held on the carrier in this manner, 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, the retention state and, ultimately, the separation ability can be changed.

The carrier used in the present invention 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 materials such as silica, alumina, magnesia, titanium oxide, glass, silicates, and kaolin, with surface additions such as silica, alumina, magnesia, titanium oxide, glass, silicates, and kaolin. Examples of surface treatment methods that may be performed include silanization using an organic silane compound and surface treatment using plasma polymerization.

When using polysaccharides or their derivatives for optical resolution, separation characteristics may vary depending on 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 the intended use. or,
Polysaccharide derivatives synthesized by heterogeneous reactions often retain the higher-order structure of the starting polysaccharide, and have a different higher-order structure even if they are chemically identical to those synthesized by homogeneous reactions, which can lead to different separations. It may give rise to certain characteristics.

In the present invention, there are no particular limitations on the developing solvent used in liquid chromatography or thin layer chromatography, except for liquids that dissolve or react with polysaccharides or derivatives thereof.

Binding the polysaccharide or its derivative to a carrier by chemical methods,
When insolubilized by crosslinking, there are no restrictions except for reactive liquids. Needless to say, the separation characteristics of acyl derivatives of amines change depending on the developing solvent, so it is desirable to consider various developing solvents.

In addition, when performing thin layer chromatography, 0.1-
0.1 mm to 100 m consisting of the separation agent of the present invention consisting of particles of the order of ~0.1 mm and, if necessary, a small amount of binder.
A layer having a thickness of m may be formed on the support plate.

[For production]

Although it is not clear why the method of the present invention effectively achieves optical resolution of enantiomeric mixtures of acyl derivatives of amines, it is not clear why the method of the present invention effectively achieves optical resolution of enantiomeric mixtures of acyl derivatives of amines. However, it is thought that this results in good optical resolution reflecting the chirality of the polysaccharide or its derivative.

〔Effect of the invention〕

As described above, the present invention has established a method for obtaining optically active acyl derivatives of amines useful as synthetic intermediates using a simple chromatography technique.

〔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 thereto.

Note that the parameters k'' and α used in the examples are defined as follows.

k- (capacity ratio) Retention time of a certain optical isomer - dead time limit
time α (separation coefficient) Example I The racemic form of N-acetyl-2-amino-4-phenylbutane was prepared by using silica gel obtained by treating cellulose tribenzoate with diphenylsilane. Merck Lichro
spher St 1000) with an inner diameter of 4, 6 ms + φ, filled with a separating agent supported at about 22% by weight.
A stainless steel column with a length of 25 cm was used as a column for liquid chromatography, eluent: n-hexane/isopropyl alcohol = 95:5, flow rate 2 liters @ 7/mi.
Optical separation was performed at a temperature of 50°C. The chromatogram at this time is shown in FIG.

The eluted optical isomer was detected using an ultraviolet detector (Shimadzu 5PD-
11) using ultraviolet absorption with a wavelength of 210 nn+. The (R) isomer and (S) isomer were determined by fractionating and purifying by a conventional method and measuring the optical rotation.

The capacity ratio (K+-+ Kz-) and separation coefficient (α) of the (R) and (S) bodies were as follows.

, −=4.86 Kz−=5.50α−1
,13

[Brief explanation of the drawing]

FIG. 1 is a diagram showing a split chromatogram obtained in Example 1.

Claims (1)

[Claims] 1. General formula (I) ▲ Numerical formula, chemical formula, table, etc.▼... (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 COR is an acyl group, and n is an integer of 1 to 3. A method for optical resolution of amine derivatives. 2. The optical resolution method according to claim 1, wherein the acyl derivative of the amine is N-acetyl-2-amino-4-phenylbutane.