KR100217842B1 - 6-dimethylsesylsylil-2,3-dimethyl beta cyclodextrin and its preparation method - Google Patents

Abstract

The present invention relates to β-cyclodextrin derivatives, and more particularly, to β-cyclodextrin derivatives useful for optical isomer separation, and having the following formula (I) in which a dimethyl cesilyl group is introduced to a carbon at position 6 New β-CD derivatives are provided which serve as stationary phases for CGC columns in the separation of racemic optically active materials.

The present invention also provides a method for preparing such β-cyclodextrin derivatives and a method for separating optical isomers using such derivatives.

Description

6-dimethylcesilsilyl-2,3-dimethyl beta cyclodextrin useful for optical isomer separation and preparation method thereof

1 is a gas chromatogram obtained by separating alcohol optical isomers using a β-cyclodextrin 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-CD having dimethylthexylsilane and methyl groups, useful as stationary phases for optical isomer separation. Derivatives, methods for their preparation 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. No. 5,064,944; 5,154,738; And 5,198,429, and the like, and these patents include alkylated hydroxy groups at the 2nd and 6th carbon positions of glucose constituting β-CD and hydroxyl groups at the 3rd position are acylated β-CD and 2,3 of glucose. (Beta) -CD etc. which fully alkylated the hydroxy group in carbon 6 are disclosed.

Recently, however, CD derivatives in which the hydroxyl group at the 6th carbon position of glucose is t-butyldimethylsilylated and the methylated or acetylated the hydroxyl group at the 2nd and 3rd carbon positions are more excellent due to the increased hydrophobicity by the t-butyldimethylsilyl group. It has been reported to exhibit enantioselectivity (α).

HRC, 15 (vol), p. 590 (1992); HRC, 15 (vol), P. 176 (1992); HRC, 16 (vol), 693 (1993)].

The present inventors have conducted research to obtain a cyclotextrin compound exhibiting excellent optical selectivity and have 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 present inventors have tested the hydroxyl group of glucose with various substituents and found that when the compound of Formula (I) is used as a stationary phase of a CGC column, It was found to be very useful for separation.

The compound of formula (I) is methylated with hydroxyl groups at the 2nd and 3rd carbon positions of glucose and 6-dimethylceylsilyl-2,3 obtained by dimethylthexylsilan at the hydroxyl position at the 6th carbon position. , -Dimethyl beta cyclodextrin, when used as a stationary phase in a CGC column, is very effective for the separation of racemic optically active substances, in particular optically active alcoholic compounds.

Coating the separation capillary column with a compound of the present invention in the preparation of a column using the cyclodextrin of formula (I) as the stationary phase of CGC can be any method known in the art. In the embodiment of the present invention J.Bouche and M. Verzele according to the coating method foamed in "J.Gas Chromat ogr. 6 (1968) 501".

In coating, the compound of the present invention is dissolved in polysiloxane used as a matrix and applied to a capillary column in a liquid state.

At this time, the polysiloxane used as the matrix is OV-1 (100 Methyl Polysiloxane), PS-086 (12-15) Phenyl, 7 Cyanopropyl, 86 Methylpolysiloxane), SE-54 (3-5 Phenyl, 1 Vinyl, 94-96 Methylpolysiloxane), and OV-1701 (7 Phenyl, 7 Cyanopropyl, 86 Methylpolysiloxane) and the like.

Among the polysiloxanes, OV-1701 is used in view of having a high solubility in the compound of the present invention, a very high wettability to adhere to the capillary inner wall, and stable and high theoretical plate number. It is preferable that the optical selectivity is excellent accordingly.

When the compound of the present invention was used as a stationary phase of a CGC column, alcohols such as 1-phenyl-1 propane, 2-phenyl-1-propane, and 1-phenyl-2-propanol were particularly effective.

Optical selectivity (α value enantiosel ectivity) obtained using 6-t-butyl dimethylsilyl-2,3-dimethyl-β-CD, a CD derivative disclosed in HRC, 16 (vo1), 693 (1993). In contrast with the separation factor α value obtained when the compound (I) of the present invention is used, the compound of the present invention is not only excellent as a whole, but also particularly excellent for the alcohol.

In addition, most CGC columns prepared using conventional CD derivatives were able to be separated after acylating the hydroxyl group of the alcohol when the alcohol compound was separated. However, when the compound of the present invention is used, the sample may not be acylated separately. There is no need for direct separation.

This is very important in terms of fundamentally eliminating the problem of derivatization in separating racemic organic materials (for example, quantitative error due to yield change, racemization during reaction, etc.).

On the other hand, according to the second aspect of the present invention, there is provided a method for producing a compound of formula (I), which method is

A first step of reacting the β-cyclodextrin compound of formula (II) with tert-butyldimethylsilyl chloride to form a β-CDsilane derivative of formula (III);

A second step of alkylating the β-CD silane derivative and methane iodide to form a dialkyl silanated β-CD derivative of Formula (IV);

A third step of reacting the derivative of Formula (IV) with tetrabutyl ammonium fluoride to remove the t-butyldimethylsilane group at the 6th carbon position of the cyclodextrin; And

A fourth step of reacting β-CD from which the t-butyldimethylsilane group of formula (V) is removed with dimethylcecylsilyl chloride; It includes.

Schematic of the method is as follows.

The reaction for forming the silane derivative of Formula (III) is 0 The reaction is carried out in the presence of a base such as pyridine in the temperature range of room temperature, wherein pyridine also serves as a solvent.

The alkylation reaction is carried out at room temperature under sodium hydride (NaOH) base, in the presence of a solvent such as N, N-dimethylformamide (N, N-dimethylformamide, DMF) or tetrahydrofuran (THF) and the third step is also tetra In the presence of a hydrofuran solvent.

In addition, the fourth step is carried out at room temperature, pyridine is used as a solvent and base.

According to a third aspect of the present invention, there is provided a method for separating optical isomers using the β-CD derivative compound of formula (I) prepared according to the above method.

In the gas chromatographic separation method of separating the optical isomer from the mixture by contacting the stationary phase and the mixture,

It is characterized by using the compound of the said Formula (I) as a stationary phase.

This method is useful for the separation of racemic isomers comprising the cyclic and racemic groups of racemic, specific examples of which are (trans) 3-penten-2-ol, (sec) -phenethyl alcohol, 1 -Phenyl-1-butanol, 1-phenyl-2- petanol, and the like.

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

Example 1

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

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

Pyridine solution 30 in which β-CD 2,31gr of the formula (II) is dissolved. 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 solid was filtered and dried and the remaining solid mixture was purified by silica gel column chromatography (eluent, methanol: methylene chloride = 1:10) to obtain 1.2 gr of pure Formula (III) compound 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 Formula (IV)

Sodium Hydride 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. Methane iodide here 1 Was slowly injected into the syringe and stirred for 4 hours. A small amount of methanol was added to the reaction mixture to terminate the reaction and water20 And ethyl acetate (20 3 times each) and concentrated under reduced pressure. Then, the resultant was purified by silica gel column chromatography (elution solvent, ethyl acetate: nucleic acid = 1:10) to give a compound of Formula (IV) 150 Was obtained as a colorless solid.

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 ), 3.9-3.60 (m, 480H), 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

(3) Synthesis of 2,3-dimethyl-β-CD Formula (V)

6-tert-butyldimethylsilyl-2,3-dimethyl-β-CD of the above formula (VI) was substituted with THF 10 THF solution of 1 mol tetrabutylammonium fluoride in 5 Add at room temperature 80 Stirred for 2 h. The reaction was terminated by TLC (thin layer chromatography, developing solvent = solution of 10% methanol in methylene chloride), THF solvent was evaporated under reduced pressure, and the remaining residue was purified by column chromatography (eluent solvent = 10). Solution of methanol in methylene chloride), and purified. Pure title compound was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.21 (m, 7H), 3.32-3.93 (m, 35H), 3.51 (s, 21H), 3.63 (s, 21H), 4.35 (br s, 7H) , 5.08 (d, 7H, J = 3.6 Hz)

(4) Synthesis of 6-dimethylcesilsilyl-2,3-dimethyl-β-CD (compound of formula (I))

2,3-dimethyl-β-CD 100 of Formula (V) Pyridine solution 2 Dimethylcecylsilylchloride 500 0 Slowly at room temperature and stirred for 4 hours at room temperature Water from 1 Terminate the reaction with methyl acetate and 10 Extracted twice. Organic layer of water 5 After washing with water, the water was removed with MgSO ₄ and then filtered and the solvent was removed under reduced pressure. The remaining residue was purified by silica gel column chromatography (elution solvent, methanol: methylene chloride = 1: 10) to obtain pure title compound 50 Was obtained as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.09 (m, 42H), 0.08 (m, 84H), 1.61 (q, 7H, J = 6, 8 Hz), 3.07 (dd, J = 9.6, 3.4 Hz ), 3.53 (s, 21H), 3.69 (s, 21H), 3.56-3.81 (m, 28H), 4.13 (d, 7H, J = 10.3 Hz), 5.21 (d, 7H, J = 3.3 Hz)

¹³ C-NMR (75 MHz, CDCl ₃ ): -2.8, -2.5, 18.9, 19.0, 20.6, 20.7, 25.4, 34.5, 58.9, 61.8, 62.4, 72.6, 79.1, 82.2, 82.5, 98.4 ppm

Example 2

[Isolation of Optical Isomers Using β-CD Derivatives]

(1) Preparation of stationary phase 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 commercially available polysiloxane (OV-1701, manufactured by Altech) in a 1: 3 weight ratio, it is methylene chloride (CH ₂ CL ₂ ) and normal 0.33 in a solution mixed with n-pentane in a 1: 1 volume ratio To dissolve. J. Bouche and M. Verzele then published J. Gas Chromatogr ,. A stationary 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

Gas chromatography detector uses a flame ionization detector (FID), and the prepared column as a stationary phase and the temperature of the sample injector is 250 Detector temperature is 300 Isomers were separated. The temperature of the GC oven is 80 Hold for 5 minutes at 140 Up to 10 per minute The temperature was raised and maintained for 25 minutes to separate the racemic cyclic alcohol and the alcohol optical isomer having a phenyl group. Sample to be separated 10 Was dissolved in 1 m of methylene chloride and injected, and the sample injection ratio was 1:30. Helium was used as the carrier gas and the inlet pressure was 14 psi.

Figure 1 shows the results of separating the racemic cyclic alcohol and the alcohol optical isomer having a phenyl group by a capillary column made by using the β-CD derivative of the present invention as a stationary phase. Sample A is (trans) -3-feten-2-ol, Sample B is (sec) -phenethyl alcohol, Sample C is 1-phenyl-1-butanol, and Sample D is 1-phenyl-2pentanol.

In addition, 6-tert-butyldimethylsilyl-2,3-dimethyl-β-cyclotextrin (Tβ-β-CD), a CD derivative having a similar structure as disclosed in the literature [HRC 16 (vol), 693 (1993)]. And a comparison value of the optical selectivity values (α values) obtained using the compound (I) of the present invention are shown in Table 1 below.

From the above test results, when the optical isomer is separated using the β-CD derivative according to the present invention, it can be seen that it shows excellent separation selectivity as compared with the conventional β-CD derivative as shown in Table 1 above.

In addition, the β-CD derivative of the present invention has a high solubility in polysiloxane OV-1701 which is used as a matrix when coated on a capillary column, and thus has a high ability to adhere to the inner wall of the capillary tube, thereby producing a very stable and large theoretical column. As a result, as shown in FIG. 1, a chromatogram having a symmetrical peak shape and a narrow peak width can be obtained.

Moreover, in the case of separating an alcohol compound by most CGC columns made of a conventional β-CD derivative, it is only possible to separate the hydroxy group after acylating the hydroxy group, but when using the β-CD derivative compound of the present invention, It can be separated directly without the process of derivatization separately. In other words, the sample can be separated without problems caused by the derivatization of the sample, that is, quantitative error due to mercury and racemization during the reaction.

Claims (5)

6-Dimethyl cesylyl-2,3-dimethyl-β-cyclodextrin compound useful as stationary phase for optical isomer separation having the structural formula (I) Reacting the β-cyclotextrin compound of formula (II) with tert-butyldimethylsilyl chloride to form a β-CD silane derivative of formula (III); Alkylating the β-CD silane derivative with methane iodide to form a dialkylsilaneated β-CD derivative of Formula (IV); Reacting a derivative of formula (IV) with tetrabutylammonium fluoride to remove the t-butyldimethylsilane group at the 6th carbon position of cyclotextrin; And reacting β-CD from which the t-butyldimethyl silane group of the following formula (V) is removed with dimethylcecylsilyl chloride; 6-dimethyl cesilsilyl-2,3-dimethyl-β-cyclodextrin production method of formula (I) comprising a. In the gas chromatography separation method of separating an optical isomer by contacting a mixture with a stationary phase, 96-56717 And the cyclodextrin derivative (I) of claim 1 as the stationary phase. The method of claim 3, wherein the optical isomer is an alcohol. The method of claim 4, wherein the alcohol is selected from the group consisting of 1-phenyl-1 propanol, 2-phenyl-1-propanol, and 1-phenyl-2 propanol.