KR100217846B1 - Beta cyclodextrin derivative which is useful for enantiomer seperation - Google Patents

Abstract

The present invention relates to β-cyclodextrin derivatives, and more particularly to β-cyclodextrin derivatives useful for optical isomer separation, wherein a new β- having a formula (I) having a silane group introduced into the carbon at position 6 CD derivatives are provided which are used as the stationary phase of a CGC column in the separation of racemic optically active materials by mixing with materials conventionally used as the stationary phase in CGC columns.

Description

Beta cyclodextrin derivatives useful for optical isomer separation

1 is a gas chromatogram obtained by separating a cyclic alcohol optical isomer using a β-cyclodextrin derivative according to the present invention.

2 is a gas chromatogram obtained by separating an alcohol optical isomer having a phenyl group using a β-CD derivative according to the present invention.

3 is a gas chromatogram obtained by separating halogenated alkane optical isomers using a β-CD derivative according to the present invention.

The present invention relates to β-cyclodextrin (hereinafter referred to as "β-CD") derivatives, and more particularly to β-cyclodextrin derivatives having alkylsilane groups useful as a stationary phase for optical isomer separation and their use.

Angewandte Chemie, 29, pp. 939-1076 (1990) and the like, when the β-CD derivative is used as a stationary phase in capillary gas chromatography (hereinafter referred to as "CGC"), it is possible to easily separate not only racemic optical isomers but also structural isomers. Known. As described above, many studies have been conducted regarding β-CD which is useful for isomer separation. Examples include US Pat. Nos. 5,064,944, 5,154,738 and 5,198,429. Patent Nos. 5,064,944 and 5,154,738 are identically fluidized with methyl, pentyl or pentyl ether hydroxyl groups at the carbon positions 2 and 6 of the glucose constituting β-CD, and the hydroxyl groups at position 3 are trifluoroacetylated. It is a mixture of isomers, not pure substances.

Further, Patent No. 5,198,429 is a pure substance obtained by derivatizing all hydroxyl groups at the 2nd and 6th positions of glucose constituting β-CD with pentyl ether, and hydroxylated at the 3rd carbon position.

The present inventors have conducted research to obtain a cyclodextrin compound exhibiting excellent optical selectivity and found a new β-CD derivative having a different chemical structure from that of a conventional cyclodextrin derivative and having better optical selectivity.

Accordingly, an object of the present invention is to provide a novel β-CD derivative, a method for preparing the same and an optical isomer separation method using the same.

According to the 1st aspect of this invention, the (beta) -CD derivative compound of following formula (I) is provided.

In order to obtain a cyclodextrin having excellent optical selectivity, the inventors tested the hydroxyl group of glucose with various substituents, and as a result, racemic optical is obtained when the compound of formula (I) is used as a fixed phase of a CGC column. It has been found to be very useful for the separation of actives.

The compound of formula (I) is 6-tert-butyldimethyl silyl-2 obtained by ethylating the hydroxyl group at the 2nd and 3rd carbon positions of glucose and tert-butyldimethylated at the 6th position of the hydroxyl group, As a 3, -dimethylbeta cyclodextrin, when used as a stationary phase in a CGC column, it is effective for the separation of racemic optically active materials, especially cyclic alkyl alcohol compounds, optical isomers of alcohols having phenyl groups. The cycloalkyl alcohol compound is 2-cyclohexen-1-ol, trans-1, 2-cyclohexanediol, and the halogenated alcohol compound is 2-bromobutane and sec-phenethyl is an alcohol having a phenyl group. Alcohol and phenyl ethyl propionate.

In addition, the β-CD derivative of the present invention reacts the β-CD compound of the following formula (1) with tert-butyldimethylsilyl chloride to obtain 6-tert-butyldimethylsilyl-β-CD of the following formula (2) This can be obtained by iodide ethanol alkylation.

The reaction to form the silane derivative of the following formula (2) is carried out in the presence of a base such as pyridine in the temperature range of 0 ℃-room temperature, wherein pyridine also serves as a solvent. In addition, the alkylation reaction uses dimethyl formaldehyde or tetrahydrofuran as a solvent to alkylate at room temperature in the presence of a sodium hydride (NaH) base.

According to a second aspect of the present invention, there is provided a method for separating optical isomers using a β-CD derivative compound of formula (I) prepared according to the above method, which comprises contacting a stationary phase with a mixture to remove the mixture from the mixture. In the gas chromatographic separation method for separating the optical isomer, the compound of formula (I) is used as the stationary phase.

This method is useful for the separation of cyclic alcohols, phenyl alcohols and halogenated alkanes which are optical isomers, and specific examples thereof include 2-cyclohexen-1-ol, (trans) -1 and 2-cyclohexane as described above. Diols, (sec) -phenethyl alcohol, phenyl ethyl propionate and bromobutane.

Hereinafter, embodiments of the present invention will be described in detail.

Example 1

[Preparation of 6-isopropyldimethylsilyl-2,3-dimethyl-β-CD (compound of formula (I))]

(1) Synthesis of 6-tert-Butyldimethylsilyl-β-CD Formula (III)

Pyridine solution 30 dissolving 2.31 g of β-CD of Formula (II) 20 dissolved in tert-butyldimethylsilylchloride 2.27gr 0 Slowly at room temperature and stirred for 8 hours at room temperature Water 50 Was added. The resulting replacement was filtered, dried and the remaining replacement mixture was purified by silica gel column chromatography (eluent, methanol: methylene chloride = 1:10) to obtain pure Formula (III) Compound (1.2 g) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.03 (s, 42H), 0.87 (s, 63H), 3.50-4.04 (m, 42H), 4.86 (d, 7H, J = 3.3 Hz), 5.23 ( s, 7H), 6.67 (s, 7H)

¹³ C-NMR (75 MHz, CDCl ₃ ): -5.2, -5.1, 18.3, 25.9, 61.7, 72.6, 73.4, 73.7, 81.8, 102.1 ppm

(2) Synthesis of 6-tert-Butyldimethylsilyl-2,3-dimethyl-β-CD (Compound of Formula (I))

Sodium hydride (NaH) 120 Dimethyl Formamide 5 In solution dissolved in 6-tert-butyldimethylsilyl-β-CD 200 0 It was added at and stirred for 30 minutes at room temperature until hydrogen evolution was complete. Iodine iodide with a syringe after that 1 Was injected slowly and stirred for 4 h. A small amount of methanol was added to the reaction mixture to terminate the reaction and water 20 And ethyl acetate 20 Three times each was extracted and concentrated under reduced pressure. Then purified by silica gel column chromatography (elution solvent, ethyl acetate: nucleic acid = 1:10) to give the title compound as a colorless solid 150 Got.

¹ H-NMR (300 MHz, CDCl ₃ ): δ-0.01 (2 xs, 42H), 0.84 (s, 63H), 1.16-1.25 (m, 42H), 3.11 (dd, 7H, J = 3.4 Hz, 9.8 Hz ), 3.48-3.60 (m, 49H), 4.00 (m, 7H), 4.10 (m, 7H), 5.18 (d, 7H, J = 5.6 Hz)

¹³ C-NMR (75 MHz, CDCl ₃ ): -5.16, -4.77, 15.74, 18.28, 25.94, 62.34, 66.44, 68.67, 72.33, 77.60, 80.16, 80.26, 98.10 ppm

Example 2

[Isolation of Optical Isomers Using β-CD Derivatives]

(1) Stationary Phase Preparation of Capillary Gas Chromatography

A fused silica capillary column (30m × 0.25mm) was used and was purchased from Alltech (USA). After mixing the β-CD derivative of formula (I) according to the present invention and a commercially available polysiloxane in a 1: 3 weight ratio, it is a solution in which methylene chloride, (CH ₂ Cl ₂ ), and normal pentane are mixed 1: 1. 0.33 in Dissolved to The polysiloxane is OV-1 (100 according to the polarity) Methyl polysiloxane), SE-54 (3-5) Phenyl, 1 Vinyl, 94-96 Methyl polysiloxane), PS-086 (12-15 Phenyl, 7 Cyanopropyl, 86 Methyl polysiloxane), OV-1701 (7 Phenyl, 7 Cyanopropyl, 86 Methyl polysiloxane), and OV-1701 is most preferably used as the polysiloxane. J. Bouche and M. Verzele then published J. Gas Chromatogr ,. The fixed phase was prepared by coating a capillary column with the solution according to the static coating method disclosed in 6 (1968) 501.

(2) Separation of racemic optical isomers

The gas chromatography detector uses a flame ionization detector (FID), and the prepared column as a fixed bed and the sample injector has a temperature of 250 Detector temperature is 300 Isomers were separated. Sample to be separated 10 Methylene chloride 1 Was injected into the sample, and the sample injection ratio was 1:30. Helium was used as the carrier gas and the inlet pressure was 14 psi.

The racemic optical isomers of each sample were separated under the temperature conditions shown in Table 1 below.

The results of separating the racemic optical isomers of the cyclic alcohol, the alcohol having a phenyl group, and the halogenated alkanes by capillary columns made by using the β-CD derivative of the present invention as the stationary phase are shown in FIGS. 1 to 3.

Also disclosed in the literature [HRC, 16 (vol), 693 (1993)] conventional 6-t-butyldimethylsilyl-2,3-dimethyl-β-cyclodextrin (TB-β-CD) and compounds of the invention The comparative values of the optical selectivity values (α values) obtained using (I) are shown in Table 2 below. According to the results of Table 2, when the racemic optical isomer is separated by a column made using the compound of the present invention, the separation selectivity of the compound is better.

In addition, the β-CD derivative according to the present invention has excellent separation selectivity of the optical isomer from the above test results, and in particular, the β-CD derivative has a large size of the cavities, unlike the α-CD derivative. Although no separation occurs, it can be seen that the compound is useful for separating optical isomers of cyclic and phenyl-containing compounds and halogenated alkanes.

Claims (6)

6-tert-Butyldimethylsilyl-2,3-diethyl-β-cyclodextrin compound useful as a stationary phase for engineering isomer separation having the structure (I) A gas chromatography separation method for separating an optical isomer by contacting a fixed phase with a mixture, wherein the cyclodextrin derivative of formula (I) is used as the fixed phase. The method of claim 2, wherein the optical isomer is an alcohol. The method according to claim 3, wherein the abnormal group alcohol is selected from the group consisting of 2-cyclohexen-1-ol, (trans) -1,2-cyclohexanediol, (sec) -phenethyl alcohol, phenyl ethyl propionate. How to feature. The method of claim 2, wherein the optical isomer is halo alkanes. The method of claim 5, wherein the halo alkanes are 2-bromobutane.