JPH089554B2 - Optical resolution method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The optically active compound obtained by the separation method of the present invention is, for example, various amino acids expected to be used as an antihypertensive agent due to angiotensin converting enzyme (ACE) inhibitory activity. It is useful as a common synthetic intermediate for derivatives. It is also expected as a starting material for various optically active substances.

(Prior Art and Problems) Until now, a method for separating the optical isomers of the double chiral compound having two asymmetric centers at once has not been known.
Therefore, after separating the diastereomers by recrystallization, a method of inducing each enantiomer into the diastereomers and performing optical resolution, an asymmetric synthesis in which a monochiral compound is used as a raw material, and the like have been performed. The former method, which uses the crystallization process, is not an efficient method because it takes a lot of time,
The asymmetric synthesis method has a problem in that a target compound having a high optical purity cannot be obtained.

(Means for Solving the Problem) The present inventors have completed the present invention as a result of intensive studies on a method for solving the above-mentioned problems. That is,
The present invention is a filler comprising an alanine derivative having two asymmetric centers represented by the following general formula (I), an optically active amino acid capable of forming a complex with a transition metal ion, or an aminoalcohol derivative derived therefrom. The present invention relates to an optical resolution method characterized in that separation is carried out by liquid chromatography using a ligand exchange filler composed of one supported on a substrate.

(In the formula, R ^{1 represents} an alkyl group or an aralkyl group, R ² represents a lower alkyl group, and * represents an asymmetric carbon.) In formula (I), the alkyl group represented by R ¹ is methyl. , Ethyl, butyl, pentyl, hexyl,
Groups such as octyl, isopropyl, sec-butyl, and aralkyl groups include benzyl group and phenylethyl group. Further, examples of the lower alkyl group represented by R ² include groups such as methyl, ethyl and propyl.

The ligand exchange type filler in the present invention comprises an optically active amino acid capable of forming a complex with a transition metal ion, or an aminoalcohol derivative derived from the amino acid supported on a filler base material. . The optically active amino acid or the amino alcohol derivative derived from the amino acid,
Examples include natural or non-natural α-amino acids, β-amino acids and amino alcohol derivatives obtained by molecular design thereof, which can form metal salts. More specifically, alanine, arginine, aspartic acid, asparagine, cysteine, glutamic acid, histidine, isoleucine, leucine, lysine, ornithine, methionine,
Phenylalanine, serine, threonine, tryptophan, tyrosine, valine, phenylglycine, proline,
Examples are metal salts of hydroxyproline, allohydroxyproline, N-carbomethyl-2-amino-1,2-diphenylethanol and the like. 2 as the metal forming the salt
Examples are valent copper, nickel, and trivalent cobalt. Examples of the filler base material include porous inorganic materials, porous synthetic polymers, and polysaccharides. More specifically, examples of the porous non-base material include glass, silica gel, diatomaceous earth, and porous synthetic polymers. Examples thereof include a styrene-divinylbenzene copolymer, a polymer of an acrylic acid ester of a polyhydric alcohol, and examples of polysaccharides include dextran and cellulose, and silica gel is most preferable. When silica gel is used as a simple substance, the filler of the present invention has the following general formula (II).
Indicated by.

(However, in the formula, at least one of Y1, Y2, and Y3 represents silica gel or a siloxane bond portion with silica gel,
The rest are hydrogen, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 14 carbon atoms, an arylalkyl group having 7 to 20 carbon atoms, a halogen, a hydroxy group, or an alkoxy group having 1 to 6 carbon atoms or any of these. Represents the combination of. X represents a spacer having 1 to 20 carbon atoms. R represents an optically active amino acid or a metal salt of an aminoalcohol derivative derived therefrom.

As the silane treating agent for forming the spacer portion of the filler represented by the general formula (II), any known one can be used, and specifically, 3-chloropropyltrimethoxysilane, 3-chloropropyldimethoxy Methylsilane, 3-chloropropylmethyldichlorosilane, 3-chloropropyltrichlorosilane, 3-bromopropyltrichlorosilane, 3-bromopropyldimethylchlorosilane, 3-bromopropyltrichlorosilane, 3-bromopropyltrimethoxysilane, 2- ( 3,
4-epoxycyclohexylethyl) trimethoxysilane, 3-glycidoxypropyltrimethoxysilane, diethoxy-3-glycidoxypropylmethylsilane, 3
-Glycidoxypropyldimethylethoxysilane 8-bromooctyltrichlorosilane and the like are exemplified.

In the separation method of the present invention, it is preferable to use the substance represented by the general formula (II) as a packing material for liquid chromatography and to use a divalent copper strong acid salt aqueous solution as a mobile phase. The strong acid salt of divalent copper is, for example, copper sulfate, cupric chloride, cupric nitrate, or a hydrate thereof, and an aqueous solution thereof is used. However, when the target substance to be separated is not soluble in the mobile phase, the target substance to be separated can be dissolved by adding an organic solvent capable of being hydrated to water. Also, when the elution time of the separation target is slow, it is possible to separate more quickly by changing the metal ion concentration in the mobile phase, changing the pH, or adding a water-soluble organic solvent. is there. Examples of the organic solvent include polar solvents such as methanol and acetonitrile.

The material of the column for liquid chromatography for separating the optical isomers of the double chiral compound represented by the above general formula (I) may be any as long as it can shield the mobile phase, but normally the working pressure and the pressure resistance of the packing material are used. Selected from ability. Any size can be used in principle, but an appropriate size is selected from the sample injection amount, analysis time, solvent flow rate and the like. In the column, each optically resolved optical isomer is detected by a detector provided at the column outlet, but any detection method may be used. The present invention is a separation method in which each of the optical isomers can be separated by connecting the column as described above to a liquid chromatograph device and injecting the compound represented by the general formula (I) into the device. .

(Effect of the invention) In the present invention, the compound having the structure of the general formula (I) which is optically resolved is, for example, an angiotensin converting enzyme (AC
E) It is useful as a common synthetic intermediate for various amino acid derivatives that are expected to be used as antihypertensive agents due to their inhibitory activity. It has been impossible to separate such a double chiral compound with high optical purity by a conventional method. However, the separation method provided by the present invention shows a very good optical resolution for the compounds of general formula (I). That is, since each optical isomer is eluted with a sufficient difference in elution time and each peak is sharply separated, each optical isomer can be obtained with high optical purity and high yield. or,
It is also an accurate analytical means for determining the qualitative and optical purity of optical isomers.

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

As the column for high performance liquid chromatography (HPLC), a column packed in a stainless steel column having a length of 250 mm and an inner diameter of 4.6 mm was used. An ultraviolet detector (Hitachi 638-41 type wavelength tunable UV monitor) was used to detect the eluted optical isomers.

(Example 1) N- [1- ethoxycarbonyl-3-phenylpropyl] - alanine _{(R1 = -CH 2 CH 2 Ph} , P2 = Me, X = COOE
t, Y = NH, Z = COOH, this compound is abbreviated as EPAL hereinafter)
Was subjected to optical resolution by a ligand exchange type filler in which proline was bound to a silica gel substrate via 3-glycidoxypropyltrimethoxysilane as a spacer.
The following conditions were used for EPAL separation.

Mobile phase: 2.5 mM CuSO4 Flow rate: 1.5 ml / min Detection: 260 nm Temperature: 50 ° C Sample injection amount: 1000 ppm x 100 μl By this resolution method, each optical isomer of EPAR is as shown in the chromatogram shown in Fig. 1. Complete separation was performed in the elution order of RS, SS, RR, RS.

(Example 2) N- [1-ethoxycarbonyl-3-methylbutyl]
- alanine _{(R1 = -CH 2 CH (CH} 3) CH 3, R2 = Me, X = COO
Et, Y = NH, Z = COOH, this combination is abbreviated as EMBA hereinafter)
Was combined with proline via a 3-glycidoxypropyltrimethoxysilane as a spacer on a silica gel substrate, and optical resolution was performed according to the ligand exchange type filler according to Example 1. As a result, the four optical isomers of EMBA were completely separated as shown in FIG.

(Example 3) EPAL is used as an amino alcohol derivative represented by the following structural formula on a silica gel substrate via 3-glycidoxypropyltrimethoxysilane as a spacer. According to the same manner as in Example 1, optical resolution was performed using a ligand-exchange type filler having a bonded group. The chromatogram is shown in FIG. In this case, 4 types of EPAL optical isomers were separated, but the elution order of each optical isomer was completely opposite to that of SR, RR, SS, RS form, unlike the case where proline was the ligand. It was

[Brief description of drawings]

1 to 3 are chromatograms obtained by HPLC analysis.

Claims (3)

[Claims] 1. A chiral center represented by the following general formula (I)
A ligand exchange type packing material is used which comprises an alanine derivative having an individual alanine derivative and an optically active amino acid capable of forming a complex with a transition metal ion or an aminoalcohol derivative derived from the amino acid derivative supported on a packing material base material. An optical resolution method characterized by separation by liquid chromatography. (In the formula, R ¹ represents an alkyl group or an aralkyl group, R ² represents a lower alkyl group, and * represents an asymmetric carbon.) 2. The optical resolution method according to claim 1, wherein the filler base material is silica gel. 3. The optical resolution method according to claim 1, wherein a divalent copper strong acid salt aqueous solution is used as a mobile phase.