JPH0478622B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a chromatographic packing material. More specifically, it relates to chromatographic packings used for the separation of various compounds, particularly for optical resolution.

(Prior Art and Problems) Most of the chromatographic packing materials disclosed so far for use in optical resolution are asymmetric compounds supported in various forms on inorganic carriers.
As the asymmetric compound, amino acids, saccharides, proteins, optically active polymethacrylic acid esters, optically active poly(meth)acrylic acid amides, optically active crown ethers, optically active fluorine-containing anthracene derivatives, etc. are said to be effective. The method of supporting on an inorganic carrier is a grafting method (for example, Japanese Patent Application Laid-open No.
50358 (see Japanese Patent Laid-open No. 50358) and a method of simply adsorbing and supporting (see, for example, Japanese Patent Application Laid-open No. 150432/1983).
However, the former method generally has poor reproducibility during the production of the separating agent, and the latter method has problems such as poor stability of the separating agent.

(Object of the Invention) In view of the above points, the present inventors conducted extensive studies with the aim of obtaining a stable separating agent with excellent reproducibility, particularly a separating agent for optical resolution. As a result, it was found that a new separating agent having a chemical structure different from conventional ones, that is, one in which an inorganic carrier grafted with aminoalkylsilane is reacted with an optically active epoxy compound and further reacted with an organic acid, can sufficiently achieve the above purpose. This discovery led to the completion of the present invention.

(Structure of the Invention) The present invention provides a packing for optical resolution characterized in that a chiral stationary phase is obtained by grafting an aminoalkylsilane onto an inorganic carrier and reacting it with an optically active epoxy compound, which is further reacted with an organic acid. It is a drug.

The novel chromatographic packing material of the present invention can be prepared by the following method. An aminoalkylsilyl group is introduced into the inorganic carrier by grafting the aminoalkylsilane and the inorganic carrier by a known method. The filler of the present invention can be obtained by subjecting this to an addition ring-opening reaction with an optically active epoxy compound in the presence of dispersant A, and then reacting the obtained chiral stationary phase with an organic acid in the presence of dispersant B. can.

Inorganic carriers used in the present invention include silica gel,
Examples include alumina and glass beads.

The aminoalkylsilane used in the present invention is represented by the following general formula [].

In the formula, X ₁ , X ₂ , and X ₃ each have a hydrogen atom and a carbon number of 1 to
20 alkyl groups, halogen atoms, hydroxy groups,
or an alkoxy group having 1 to 20 carbon atoms, or any combination thereof. R ₁ is carbon number 1-30
A group that forms a spacer and contains one or more amino groups at the end or inside. Specific examples of the aminoalkylsilane represented by the general formula [] include the following.

2-aminoethyltriethoxysilane, 3-aminopropyldimethylethoxysilane, 3-aminopropylmethyldiethoxysilane, 3-aminopropyltriethoxysilane, 3-aminopropyltrimethoxysilane, 1-(3-aminopropyl)- 1-Methylsiler-11-crown-4,N
-Methyl-3-aminopropyltrimethoxysilane, N-methyl-3-aminopropyltriethoxysilane, N-(2-aminoethyl)-3-aminopropyltris(2-ethylhexoxy)silane, N-(2-amino ethyl)-3-aminopropyltrimethoxysilane, N-(2-aminoethyl)
-3-aminopropylmethyldimethoxysilane,
(aminoethylaminomethyl)phenethyltrimethoxysilane, 4-aminobutyltriethoxysilane, 4-aminobutyldimethylmethoxysilane, 3-aminopropyltrichlorosilane, N-
Methyl-3-aminopropyltrichlorosilane.

The optically active epoxy compound used in the present invention is represented by the following general formula [].

In the formula, * represents an asymmetric carbon. In the formula, R ₂ is a chain or cyclic alkyl group, alkenyl group, aryl group, halomethyl group, alkoxymethyl group, thioalkoxymethyl group, aryloxymethyl group, thioaryloxymethyl group, which may have a substituent, or Represents a carboxymethyl group. Specific examples of the optically active epoxy compound represented by the general formula [] include the following.

Propylene oxide, 1,2-epoxyheptane, 1,2-epoxydecane, 1,2-epoxytetradecane, 1,2-epoxyoctadecane,
Styrene oxide, epichlorohydrin, epipromohydrin, epiiodohydrin, methyl glycidyl ether, propyl glycidyl ether,
Octyl glycidyl ether, allyl glycidyl ether, triphenylmethyl glycidyl ether, 2,2,2-trifluoroethyl glycidyl ether, 2,2,2-trichloroethyl glycidyl ether, hexafluoroisopropyl glycidyl ether, phenyl glycidyl ether,
3-Trifluoromethylphenylglycidyl ether, 2,4,5-trichlorophenylglycidyl ether, 2-chlorophenylglycidyl ether, 2-fluorophenylglycidyl ether, pentafluorophenylglycidyl ether, 3,5-dimethoxyf enyl glycidyl ether, 2,3,5-trimethylphenyl glycidyl ether, 2,4-dinitrophenyl glycidyl ether, 1-naphthyl glycidyl ether,
2-naphthyl glycidyl ether, 9-anthryl glycidyl ether, 1-anthryl glycidyl ether, 2-anthryl glycidyl ether, l-menthyl glycidyl ether, phenyl glycidyl thioether, 4-chlorophenyl glycidyl thioether, 2-naphthyl glycidyl thioether , 2-phenylbutyl glycidyl ether, 3-phenylbutyl glycidyl ether, 1-glycidyl naphthoate, glycidyl benzoate, glycidyl 2-chlorobenzoate, glycidyl 2-fluorobenzoate, glycidyl 2-iodobenzoate, 2- Glycidyl phenylbenzoate, glycidyl triphenyl acetate, glycidyl 3-phenylbutyrate, glycidyl abietate, glycidyl deoxycholate.

The amount of optically active epoxy compound is 0.01 to 0.01 by weight relative to the inorganic carrier into which aminoalkylsilyl groups have been introduced.
Use 5 times the amount, preferably 0.02 to 1 times the amount. If the amount is less than 0.01 times, the separation power is insufficient, and if the amount exceeds 5 times, the separation power will no longer improve.

The dispersant A is preferably one that dissolves the optically active epoxy compound, and examples thereof include dimethyl sulfoxide, dimethyl formamide, diglyme, triglyme, dibutyl ether, benzene, toluene, and chloroform.

The reaction temperature is 0 to 200°C, preferably 40 to 200°C.
The temperature is 120℃. During the reaction, it is desirable to perform stirring so that the concentration of the optically active epoxy compound is as uniform as possible.

The chiral stationary phase obtained by the above reaction of the inorganic carrier into which an aminoalkylsilyl group has been introduced and the optically active epoxy compound is reacted with an organic acid as follows.

The organic acids used in the present invention preferably have strong acid strength, such as 2,4-dinitrobenzoic acid, 2,6-dinitrobenzoic acid, 3,4-dinitrobenzoic acid, 3,5-dinitrobenzoic acid, and benzene. Examples include aromatic carboxylic acids or sulfonic acids such as sulfonic acid, toluenesulfonic acid, and 2,4-dinitrobenzenesulfonic acid, but non-aromatic acids such as trichloroacetic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid can also be used. be able to.

Dispersant B includes aliphatic or alicyclic hydrocarbons which may have substituents such as hexane, heptane, cyclohexane, 1,2-dichloroethane, dichloromethane, chloroform, benzene, toluene,
Aromatic hydrocarbons that may have substituents such as xylene and chlorobenzene, chain or cyclic ethers such as diethyl ether, dimethoxyethane, tetrahydrofuran, and dioxane, methanol, ethanol, isopropanol, glycerin, ethylene glycol, oftanol, etc. Examples include alcohols, acetone, ketones such as cyclohexanone, and the like.

The reaction with an organic acid can be carried out in a conventional reactor such as a flask, but more conveniently it can be carried out in a column.

In the former method carried out in a reactor, the chiral stationary phase is dispersed under stirring in a solution of dispersant B containing an organic acid in an amount of 0.01 to 10 times the weight of the chiral stationary phase. The organic acid concentration in dispersant B is
0.01-80% by weight is preferred.

The reaction temperature is usually in the range of -100 to 100°C, and the reaction time is 1 to 60 minutes. It is desirable to wash the generated filler with dispersant B.

In the latter method, a chiral stationary phase is packed in a predetermined column in advance, and a predetermined amount of an organic acid dispersant B solution is flowed into the column using an ordinary liquid chromatography device. conduct.

An organic acid in an amount of 0.01 to 10 times the amount of the chiral stationary phase packed in advance is dissolved in dispersant B to give a concentration of 0.01 to 80% by weight, and a solution is flowed into the column. After flowing the solution, it is desirable to further flow dispersant B through the column for washing.

When performing separation using the packing material of the present invention, it is necessary to select a solvent suitable for liquid chromatography, that is, a solvent that is a good solvent for the substance to be separated and has excellent separation ability. .

(Effects of the Invention) The filler for optical resolution of the present invention is effective for rapid separation of various compounds, particularly extremely effective for rapid separation of optical isomers, and has excellent reproducibility and physical and chemical stability. It is. One of the optical isomers to be separated is selectively and strongly adsorbed by the filler of the present invention.

This will be explained in more detail below using examples.

Example 1 R-(-)-epichlorohydrin (optical purity 99%
ee) 3-trifluoromethylphenol in 6.6g
Dissolve 4.63g at 80℃ in the presence of 0.08g piperidine.
Let it react for 6 hours. After excess epichlorohydrin was distilled off under reduced pressure, the residue was dissolved in 40 ml of acetone, 15 g of anhydrous potassium carbonate was added thereto, and the mixture was reacted under stirring and reflux for 6 hours. After the reaction, the acetone was distilled off, and the residue was chromatographed using alumina with a benzene eluent to obtain 5.15 g of optically active (+)-3-trifluoromethylphenyl glycyl ether ( Yield 83%, [α] _D
= +8.79°).

20g of silica gel (particle size 5μm, pore size 120Å)
After drying under reduced pressure at 120℃ for 5 hours, 18.8g of 3-aminopropyltriethoxysilane was dissolved in dehydrated toluene.
Add to the solution dissolved in 300 ml and stir under reflux for 6 hours. Filter the reaction mixture and add 300ml of toluene to the residue.
After washing with 300ml of acetone and drying at 60℃ for 12 hours, 3-aminopropylsilylated silica gel (hereinafter referred to as
It's called APS. ) was obtained. The elemental analysis values of this product were C: 4.54% and N: 1.25%.

Next, 10 g of the above APS was added to a solution of 2.0 g of the above (+)-3-trifluoromethylphenyl glycidyl ether dissolved in 40 ml of dimethylformamide, and the mixture was stirred at 80°C for 6 hours. After the reaction, the residue was washed with methanol and dried at 60°C for 12 hours to obtain a chiral stationary phase into which (+)-3-trifluoromethylphenyl glycidyl ether was introduced. The elemental analysis value of this product is C: 9.30%, N:
It was 1.07%.

The chiral stationary phase obtained in this way was
The slurry was packed into a stainless steel column of 4.6 mm and length of 300 mm, and this column was set in high performance liquid chromatography.

Add 80 ml of tetrahydrofuran to this column in order.
A solution of 4.24 g of 3,5-dinitrobenzoic acid dissolved in 80 ml of tetrahydrofuran was passed through the column at a flow rate of 2 ml/min using 80 ml of tetrahydrofuran as a mobile phase to obtain the desired column.

Using this column, (±)-2,
2'-dihydroxy-1,1'-binaphthyl was analyzed and the chromatogram shown in Figure 1 was obtained.

Temperature: Room temperature Mobile phase: n-hexane/1,2-dichloroethane/ethanol = 70:29:1 Flow rate: 2 ml/min Detector: Ultraviolet absorption meter (wavelength 254 mm) Peak number 1 in Figure 1 is (-)-2 , 2'-dihydroxy-1,1'-binaphthyl, 2 is (+)-2,
The peaks were 2'-dihydroxy-1,1'-binaphthyl, and the retention times were 16.0 minutes and 17.4 minutes, respectively.

After the above analysis, 1,2-dichloroethane was used as the eluent, followed by methanol/water = 7:3, and then analysis was performed again under the same conditions using the same three-element eluent as above, and it was found to be reproducible. A chromatogram was obtained.

In addition, using a column packed with a chiral stationary phase before reacting with 3,5-dinitrobenzoic acid,
When the same (±)-2,2'-dihydroxy-1,1'-binaphthyl was analyzed under the same conditions as above,
The retention time is 43.0 minutes for (-)- body and 47.8 minutes for (+)- body.
It was hot in minutes. It can be seen that the target filler is modified with 3,5-dinitrobenzoic acid.

Example 2 In the same manner as in Example 1, in the presence of 0.07 g of piperidine, 7.0 g of R-(-)-epichlorohydrin and 2,4,
By reaction with 5.98 g of 5-trichlorophenol, 5.91 g of optically active (+)-2,4,5-trichlorophenyl glycidyl ether was obtained (yield 77
%, [α] _D = +5.75°).

Furthermore, in the same manner as in Example 1, 10 g of APS was reacted with 2.0 g of the above (+)-2,4,5-trichlorophenyl glycidyl ether to obtain (+)-2,4,
A chiral stationary phase incorporating 5-trichlorophenyl glycidyl ether was obtained. The elemental analysis values of this product were C: 7.92% and N: 1.09%.

The obtained chiral stationary phase was prepared with an inner diameter of 4.6 mm and a length of 150 mm.
The slurry was packed into a stainless steel column (mm) and set in high performance liquid chromatography.

Add 80 ml of tetrahydrofuran to this column in order.
A solution of 2.12 g of 3,5-dinitrobenzoic acid dissolved in 80 ml of tetrahydrofuran was passed through the column at a flow rate of 2 ml/min using 80 ml of tetrahydrofuran as a mobile phase to obtain the desired column.

Using this column, (±)-2,
2'-dihydroxy-1,1'-binaphthyl was analyzed and the chromatogram shown in Figure 2 was obtained.

Temperature: Room temperature Mobile phase: n-hexane/1,2-dichloroethane/ethanol = 70:29:1 Flow rate: 1 ml/min Detector: Ultraviolet absorption meter (wavelength 254 mm) Peak number 1 in Figure 2 is (-)- 2,2'-dihydroxy-1,1'-binaphthyl, 2 is (+)-2,
The peaks were 2'-dihydroxy-1,1'-binaphthyl, and the retention times were 16.2 minutes and 17.0 minutes, respectively.

In addition, the same (±)-dihydroxy-1,
When 1'-binaphthyl was analyzed, the retention time was 33.6 minutes for the (-)-form and 36.7 minutes for the (+)-form.
It can be seen that the target filler is modified with 3,5-dinitrobenzoic acid.

Furthermore, the reaction of 2.0 g of (-)-2,4,5-trichlorophenyl glycidyl ether with 10 g of APS was repeated again, and analysis was performed under the same conditions as above. As a result, the reproducibility was within the error range. A chromatogram was obtained.

[Brief explanation of drawings]

1 and 2 are chromatograms obtained in Examples 1 and 2, respectively, where the vertical axis represents intensity and the horizontal axis represents retention time (minutes).

Claims (1)

[Claims] 1. A filler for optical resolution comprising a chiral stationary phase obtained by grafting aminoalkylsilane onto an inorganic carrier and reacting the graft with an optically active epoxy compound, which is further reacted with an organic acid.