JPS60115855A - Packing material for separation - Google Patents

Abstract

PURPOSE:To enable optical resolution of a racemic compd., more particularly amino acid with high separating efficiency by bonding a specific compd. having asymmetric carbon atom on a silica gel carrier and using the same as a packing material for sepn. CONSTITUTION:The packing material for sepn. expressed by the formula I [one ore more among Y<1>, Y<2>, Y<3> denote a silica gel and the siloxane bond part with the silica gel, the rest denotes respectively H, 1-20C alkyl, 6-20C aryl, 7-20C aryl alkyl, halogen, OH or alkoxy or an optional combination thereof, either one of X<1>, X<2> is OH and the other is the optically active group expressed by the formula II, A denotes 2-3C (substd.)alkylene, B denotes the metal salt of carboxylic acid and an asterisk mark * denotes an asymmetrical carbon atom] is used for a liquid chromatography. For example, the packing material expressed by the formula III (one of R, R' is CH3 or silica gel or both are CH3 or silica gel) is used. The efficient resolution of racemic modification of amino acid in particular is thus made possible.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel separation packing material, particularly a liquid chromatography packing material for optically resolving racemic compounds. The separating packing material proposed by the present invention uses silica gel as a carrier, and a silanizing agent is added to the carrier [2].
-(7-Ogisapicyclor4.1.O)hept-3-yl)ethylene] is chemically modified by silane reaction, and further added with D or L optically active 2-azetidinecarboxylic acid, proline, hydroxyproline and alloproline. It is made by chemically bonding any copper salt selected from hydroxyproline.

Conventional fillers for optical resolution made by chemically bonding optically active proline or hydroxy-10 phosphorus to silica gel include J. HighResol by G-Gubitz et al.
ut-Chromatogr and Chromat
ogr, Comm.

2, 145 (1979), or by Sugden et al., J. Chromatogr., 192. 228(
1980) or Angew-Chem, Int-Ed-Engl by V. A. Davankov et al.
,, 21. 930 (1982) (all of which have a carboxyl group coordinately or ionically bonded to a copper ion, and the respective enantiomers of racemic amino acids that can coordinate to this carboxyl group). Racemates are separated using differences in free energy of interaction, and various silane treatment agents have been used to chemically bond optically active groups to silica gel.

The present inventors have arrived at the present invention as a result of various studies to further improve the performance of these known separation fillers.

That is, in the above-mentioned splitting mechanism, it is thought that the steric bulk of the silane treatment agent, the distance between the silica gel and the optically active group, and the magnitude of hydrophobicity have considerable effects on the splitting ability.

As a result of intensive studies, the present inventors found that (
2-(7-oxabicyclo[4,1,o-)hept-3
It was discovered that by using ethylcosilane, the steric regulation of the fixed optically active ligand and the increase in hydrophobicity were simultaneously achieved, thereby significantly improving the resolving power compared to conventional resolving agents. A separation filler was obtained.

That is, the present invention provides a separation filler 1 comprising a substance represented by the following general formula (1) [However, in the formula, Y1. Y2. Of Y3, a small number (one represents silica gel and a siloxane bonding moiety with silica gel, and the rest are hydrogen, an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms, and an aryl group having 7 to 20 carbon atoms, respectively) It represents an alkyl group, a halogen, a hydroxy group, an alkoxy group having 1 to 20 carbon atoms, or any combination thereof. Either one of X"+X2 is a hydroxy group, and the other is an optically active group represented by the general formula , A represents an alkylene group having 2 or 3 carbon atoms, the alkylene group may have a substituent, B represents a carboxylic acid metal salt group, and the red stamp represents an asymmetric carbon atom. ] The separating packing material of the present invention can be packed into a metal or glass cylinder and used for optical resolution of racemic compounds using a conventional liquid chromatogram device.

Since the shunt filler of the present invention made of the substance represented by the above general formula (I) is made by bonding an optically active group to silica gel via a silane treatment agent, each of these will be explained below.

(A) Silica gel as a raw material has a particle size of 01 μm to 1000 μm, and a pore size of IOA to 10000 A can be used. Preferably, the particle size is 11 zm.

(B) Silanizing agent The silanizing agent forming the characteristic part of the filler of the present invention is represented by general formula (II).

In the formula, z, z', i' may be the same or different,
At least one is a halogen, a hydroxy group, or an alkoxy group having 1 to 20 carbon atoms, and the remaining are hydrogen, an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms,
It represents an arylalkyl group having 7 to 20 carbon atoms, a halogen, a hydroxy group, an alkoxy group having 1 to 20 carbon atoms, or any combination thereof.

(C) Optically active basic optically active group R forming the characteristic part of the filler of the invention is:
It is represented by the following general formula (1).

[In the formula, A: represents an alkylene group having 2 or 3 carbon atoms, and the alkylene group may have a substituent.

B: Base band mark of metal salt of carboxylic acid: asymmetric carbon atom] Specifically, 9 or L of optically active 2-acetidine carboxylic acid, proline, hydroxyproline, and allohydroxyproline selected from Either one of the two bodies can be used (the easily available L body is usually used).

The method for producing the separation filler of the present invention from the starting materials (5), (i3), and (C) above includes treating silica gel with silane and then bonding an optically active group, or combining it with a silane treatment agent. Any method of reacting with silica gel to which an optically active group has been bonded in advance is possible. Further, the reaction of converting a carboxyl group or its ester into a metal salt of thiocarboxylic acid may be carried out before bonding with silica gel (or may be converted after bonding. This metal salt may be converted into a copper salt of a strong acid). Copper salts can be obtained by the exchange reaction of

As described above, the separation packing material of the present invention is a substance formed by chemically bonding an optically active group to silica gel via a silane treatment agent, and is used as a packing material for liquid chromatography, particularly for the optical resolution of amino acids. It is suitable for use.

Synthesis examples and examples of the separation filler of the present invention will be shown below together with comparative examples, but the present invention is not limited to these examples.

Synthesis Example 1゜Silica gel was heated at 120-1 for 2-10 hours in a stream of dry nitrogen.
Heat to 50°C and dry. Dried silikage #20
g was suspended in 100 ml of anhydrous benzene, 8 g of trimethoxy[2-(7-oxabicyclo(4,t,O)hept-3-yl)ethylcosilane] was added thereto, and the mixture was heated to reflux under a stream of dry nitrogen.

The methanol generated at this time should be removed from the system.
Allow to react for ~10 hours. After the reaction is completed, the mixture is cooled to room temperature and filtered through a glass filter. The obtained modified silica gel is washed with anhydrous benzene and then dried in vacuo at 40°C. L
- Dissolve 5.6 g of proline sodium salt in 250 scraps of anhydrous dimethylformamide at 90°C, and add 2-(3
, 4-Evoxinchlorohexylethyl) silyl group was added and suspended at 90°C.
Shake for 4 hours. After that, it was cooled to room temperature, and the obtained modified silica gel was filtered once and washed with methanol.
9 was dissolved in 100 ml of pure water and transferred to an aqueous solution to prepare a copper salt. By filtering this again and washing with pure water, L-
Silica gel chemically bonded with copper salt of proline was obtained.

The structural formula of the obtained substance is estimated to be as follows.

H ■ 0=C-0-Cu'12 and 0=C-()-CIJ','2 (both R and R' are methyl groups, or both or either Example 1: The filler obtained in Synthesis Example 2 above was applied to a fully porous silica gel with an average particle size of 10 μm and an average pore size of 100 A using a high-performance liquid chromatograph. stainless steel column (i oCn
Lx O, 46 cm).

Optical resolution of the amino acid racemate was carried out using a 5 x 10' VI copper nitrate aqueous solution as a solvent at a flow rate of 2 m 7 minutes and a temperature of 50°C, as shown in Table 1 (good resolution results were obtained).

Table-1 Answer Amount Ratio Separation coefficient Separation degree Threonia 9.00 6.00 1.50 1.41
Serine 10.3 6.75 1.52 1.56 Proline 7.25 12.4 1.71 1.28 Histidine 12.6 7.50 1.68 1.14 Isoleucine 12.5 7.50. 1.67 1.74 Methionine 12.5 10.3 1,22 0.62 Valine 14.4 9.00 1.60 1.59 Phenylalanine 32.4 13.6 2.38 2.56
Tributophan 111.5 32.5 3.43 4
．． In Table 13, k, α, and R are defined as follows.

Comparative Example 1゜A silica gel filler having the following structural formula obtained in the same manner as in Synthesis Example 1 using glycidoxyglobyl trimethoxysilane as the silane treatment agent was used in a stainless steel filler with the same diameter and length as in Example 1, 25 cmrrL. As a result of filling the column and performing optical resolution of amino acids under the same conditions, the separation coefficients of isoleucine, methionine, valine, phenylalanine, and human lifthan were 1.47.1.14.1.52, respectively.
．． It was 2.08.3.14.

Structural formula (R and ri indicate that one or both of them is a methyl group, or that both or one of them are the same silica gel.) Patent applicant Daicel Chemical Industries, Ltd. Procedural amendment (Spontaneous) 1 October 22, 1982 [] 1. Indication of the case Japanese Patent Application No. 150383/1983 2. Name of the invention Separating filler 3. Relationship with the case of the person who does the printing process Details of the patent applicant Column 5 of the Detailed Description of the Invention of the Book, Contents of Amendment (1) Lines 4 to 7 on page 3 of the specification are amended as follows.

r? , +45 (+979), or Sug
Den et al. J, Chromatogr, 182.
228 (1880), or V.

A. Angew, Chem, by Davankov et al.
Int, Ed.

(1) The formula on page 4, line 11 is revised as follows.

r XI (1) 2 places on line 7 from the bottom of page 7, line 6 from the bottom of page 7, 9
Replace each “proline” in line 7 on page 7 and line 16 on page 9 with “proline”
Changed to

Procedure Amendment (Method) % Formula % 1. Indication of the case 1982 Patent Application No. 150383 2. Name of the invention Separating filler 3. Person making the amendment Relationship to the case Patent applicant December 1988 18th (Delivery date) 5. Subject of amendment Procedural amendment (voluntary) dated October 22, 1980 Manabu Shiga, Commissioner of the Japan Patent Office 1. Indication of the case 1982 Patent Application No. 150383 2, Name of the invention Separating filler 3, Relationship with the case of the person making the amendment Patent applicant representative Kubo 1) Mi Bun 4, Subject of the amendment/Details of the invention in the specification Description field

Claims (1)

[Claims] A separation filler XI consisting of a substance represented by the following general formula (1) [However, in the formula, Y', Y2. At least 1 of Y”
One represents silica gel and a siloxane bonding portion with silica gel, and the remaining represent hydrogen, an alkyl group having 1 to 20 carbon atoms, an aryl group having 6 to 2 degrees of carbon atoms, and a siloxane bonding portion with 7 to 20 carbon atoms, respectively.
Arylargylno, (represents a halogen, a hydroxy group, an alkoxy group having 1 to 20 carbon atoms, or any combination thereof. Either one of X and X is a hydroxy group, and the other is represented by a general book) It is an optically active group, A represents a fullkylene group having 2 or 3 carbon atoms, the alkylene group can have a substituent, B represents a carboxylic acid metal salt group, and the red stamp indicates an asymmetric carbon Indicates an atom.]