JP2005298574A - Substituted cyclodextrin and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an optically active column packing material for gas chromatography which shows excellent separability to a wide range of enantiomers. <P>SOLUTION: There is provided a substituted cyclodextrin represented by formula (1), wherein R<SB>1</SB>denotes a t-butyldimethylsilyl group, a triisopropylsilyl group or a t-butyldiphenylsilyl group; R<SB>2</SB>denotes an alkoxymethyl group which may optionally be substituted; and n is 6, 7 or 8. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a substituted cyclodextrin and a process for producing the same, and more specifically, a substituted cyclodextrin particularly useful as an optically active column packing material for gas chromatography capable of easily separating optical isomers that have been difficult to separate conventionally. And its manufacturing method.

  A method for directly separating enantiomers by gas chromatography equipped with an optically active stationary phase is known (see Non-Patent Document 1). In this method, the column filler containing the optically active compound is conventionally used in various methods, for example, a column method in which a column is loaded on a stationary phase carrier and a capillary column method in which an inner surface of a capillary column is coated. An optical isomer separation column has been prepared using. Until now, as an optically active compound for preparing an optically active column filler, for example, (1) L-amino acids such as L-valine, L-leucine, L-phenylglycine derivatives, (S) -1- Optically active amide compounds derived from optically active amines such as (1-naphthyl) ethylamine derivatives, optically active carboxylic acids such as chrysanthemic acid derivatives; (2) 3-trifluoroacetyl- (1R) -camphor, N- Optically active metal complexes such as salicylidene- (R) -2-amino-1,1-di (5-t-butyl-2-octyloxyphenyl) -1-propanol; (3) sugar derivatives such as cyclodextrin derivatives, etc. Various compounds have been proposed. In particular, with regard to the cyclodextrin derivative (3), many reports have been made on its application to separation of optical isomers of various essential oils and perfume compounds (see Non-Patent Document 2).

Separation of enantiomers by the optically active stationary phase prepared by the method as described above is because the stationary phase is optically active, so that the (R)-and (S) -isomers of the solute enantiomer in the mobile phase This is done by producing a diastereomeric difference in the retention force on the stationary phase. The coercive force acting between the stationary phase and the mobile phase is mainly a hydrogen bond in the stationary phase of the type (1), a coordination bond in the type (2), and a steric interaction in the type (3). It is said that hydrophobic interaction is working. Therefore, the difference in the interaction energy between the (R) -form and (S) -form of the enantiomer is so remarkable that the resolution is excellent.
S. Allenmark, “Chromatographic enantiopation,” Ellis Horwood Ltd. , Chichester (1988) Z. Lebensm. Unters. Forsch. , 196, p. 307-328, 1993

  However, the conventional fillers have a limited range of enantiomeric samples that can be applied. This is because, as described above, the interaction force that works effectively for enantiomeric identification is limited for each filler. Therefore, in order to separate a sample containing multi-component enantiomers, it is necessary to use many kinds of enantiomer separation columns, which is expensive in cost and takes a long time for separation. There is a drawback. Against this background, development of an optically active column packing material for gas chromatography that can be easily prepared and exhibits excellent resolution for a wide range of enantiomers having various functional groups is strongly desired. ing.

  Accordingly, a main object of the present invention is to provide an optically active column packing material for gas chromatography that can be easily prepared and exhibits excellent resolution for a wide range of enantiomers.

  As a result of intensive studies to solve the problems as described above, the present inventors have now optionally substituted the 2- and 3-positions of the cyclodextrin derivative as the optical isomer separation liquid phase. The present inventors have found that an optically active separation column filler exhibiting an excellent resolution for a wide range of enantiomers can be obtained by bonding a good alkoxymethyl group, and the present invention has been completed.

  Thus, the present invention provides the following formula (1):

Wherein R ₁ represents a t-butyldimethylsilyl group, a triisopropylsilyl group or a t-butyldiphenylsilyl group, R ₂ represents an optionally substituted alkoxymethyl group, and n represents 6, 7 Or 8)
The substituted cyclodextrin represented by these is provided.

  The present invention also provides an optically active column packing material for gas chromatography comprising the above-mentioned substituted cyclodextrin.

  Furthermore, the present invention provides the following formula (2):

(Wherein R ₁ and n are as defined above)
A cyclodextrin derivative represented by the following formula (3)

(Wherein R ₂ has the same meaning as described above, and X represents a halogen atom)
The following formula (1) characterized by reacting with an alkoxymethyl halide represented by the formula:

(Wherein R ₁ , R ₂ and n are as defined above)
A process for producing a substituted cyclodextrin represented by the formula:

  The substituted cyclodextrin represented by the formula (1) of the present invention exhibits excellent resolution for a wide range of enantiomers as an optically active column packing material for gas chromatography.

  Hereinafter, the present invention will be described in more detail.

In the formula (1), the alkoxy moiety of the “alkoxymethyl group” represented by R ₂ can be linear or branched, and specifically includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy And alkoxy groups having 1 to 6 carbon atoms such as t-butoxy are included. In addition, the alkoxy moiety may further include an alkoxy group such as methoxy and ethoxy; a trialkylsilyl group such as trimethylsilyl, triethylsilyl, and ethyldimethylsilyl; an aromatic dimethylsilyl group such as phenyldimethylsilyl; a trichloromethyl group, It may be substituted with a group such as a halogenated alkyl group such as a fluoromethyl group.

  Thus, specific examples of the “alkoxymethyl group” include, for example, methoxymethyl, ethoxymethyl, 2-methoxyethoxymethyl, 2-trimethylsilylethoxymethyl, (phenyldimethylsilyl) methoxymethyl group, tertiary butoxymethyl group, Examples include 2,2,2-trichloroethoxymethyl group, 2,2,2-trifluoroethoxymethyl group, 4-pentenyloxymethyl group and the like.

Specific examples of the substituted cyclodextrin represented by the formula (1) of the present invention are as follows:
6-Ot-butyldimethylsilyl-2,3-di-O-methoxymethyl-α-cyclodextrin, 6-Ot-butyldimethylsilyl-2,3-di-O-ethoxymethyl-α-cyclo Dextrin, 6-Ot-butyldimethylsilyl-2,3-bis-O- (2-methoxyethoxymethyl) -α-cyclodextrin, 6-Ot-butyldimethylsilyl-2,3-bis-O Substituted α-cyclodextrins such as-(2-trimethylsilylethoxymethyl) -α-cyclodextrin;
6-Ot-butyldimethylsilyl-2,3-di-O-methoxymethyl-β-cyclodextrin, 6-Ot-butyldimethylsilyl-2,3-di-O-ethoxymethyl-β-cyclo Dextrin, 6-Ot-butyldimethylsilyl-2,3-bis-O- (2-methoxyethoxymethyl) -β-cyclodextrin, 6-Ot-butyldimethylsilyl-2,3-bis-O -Substituted β-cyclodextrin such as (2-trimethylsilylethoxymethyl) -β-cyclodextrin;
6-Ot-butyldimethylsilyl-2,3-di-O-methoxymethyl-γ-cyclodextrin, 6-Ot-butyldimethylsilyl-2,3-di-O-ethoxymethyl-γ-cyclo Dextrin, 6-Ot-butyldimethylsilyl-2,3-bis-O- (2-methoxyethoxymethyl) -γ-cyclodextrin, 6-Ot-butyldimethylsilyl-2,3-bis-O -Substituted γ-cyclodextrins such as (2-trimethylsilylethoxymethyl) -γ-cyclodextrin, and the like.

  The substituted cyclodextrin represented by the formula (1) of the present invention is represented by the following formula (2):

(Wherein R ₁ and n are as defined above)
A cyclodextrin derivative represented by the following formula (3)

(Wherein R ₂ has the same meaning as described above, and X represents a halogen atom, particularly a chlorine atom)
It can synthesize | combine easily by making it react with the alkoxymethyl halide represented by these.

  The cyclodextrin derivative represented by the above formula (2) used as a starting material in the above reaction is known per se and can be easily obtained, for example, by reacting cyclodextrin with a halogenated alkylsilane. (See, for example, Carbohydrate Res, 192, P. 366-369, 1989), or a commercially available product. Examples of the alkoxymethyl halide represented by the above formula (3) include chloromethyl methyl ether, chloromethyl ethyl ether, 2-methoxyethoxymethyl chloride, 2-trimethylsilylethoxymethyl chloride and the like.

  The reaction between the cyclodextrin derivative represented by the formula (2) and the alkoxymethyl halide represented by the formula (3) is usually about −5 ° C. to about 120 ° C., preferably about 0 ° C. to about 60 ° C. The reaction can be performed at a temperature within the range, and can be completed in about 3 hours to about 24 hours. The amount of the alkoxymethyl halide of formula (3) is not particularly limited, but can generally be in the range of about 8 mol to about 20 mol per mol of hydroxyl group of the cyclodextrin derivative of formula (2). This reaction is preferably carried out in the presence of a catalyst. Examples of the catalyst that can be used in this case include tertiary amines such as diisopropylethylamine and N, N-dimethylaminoviridine.

  Moreover, as an organic solvent which can be used for this reaction, a dichloromethane, chloroform, a pyridine, N, N- dimethylformamide etc. can be mentioned, for example. The amount of these organic solvents to be used is not particularly limited, but usually it is preferably within the range of about 20 to about 150 parts by weight per part by weight of the cyclodextrin derivative of formula (2). After completion of the reaction, the substituted cyclodextrin of the formula (1) can be obtained with high yield and high purity by appropriately treating with ordinary separation means such as washing, extraction, drying, distillation, column chromatography and the like.

  The substituted cyclodextrin represented by the formula (1) of the present invention can be used as an optically active column packing material for gas chromatography, whereby various compounds can be separated. Excellent effect for optical resolution of enantiomers, which was difficult to separate by graphy. The optically active column packing material for gas chromatography containing the substituted cyclodextrin represented by the formula (1) of the present invention as an active ingredient is capable of separating compounds having various functional groups on the same column. Has excellent features.

  In order to pack the column for packing for gas chromatography of the present invention into a column, a conventionally used method, for example, a packed column method in which the column is loaded on a stationary phase carrier, the inner surface of the column only with the stationary phase is used. A capillary column system that coats can be used as it is. In the packed column system, for example, an optical isomer separation liquid phase composed of the substituted cyclodextrin of the formula (1) of the present invention is uniformly adsorbed in advance on a porous carrier such as silica gel, glass beads, diatomaceous earth, and alumina. It can be carried out. The porous carrier that can be used is not particularly limited. For example, a spherical carrier having a particle size of 1 to 100 μm and a pore size of 50 to 500 angstroms can be preferably exemplified. In the capillary column method, for example, an optical isomer separation liquid phase is previously applied to the inner surface of a glass or stainless steel capillary column having an inner diameter of 0.1 to 0.5 mm and a length of 10 to 100 m in this field such as a dynamic method or a static method. It can be performed by uniformly coating using a known technique.

  Hereinafter, the present invention will be described more specifically with reference to examples and comparative examples.

Example 1: Synthesis of 6-Ot-butyldimethylsilyl-2,3-di-O-methoxymethyl-β-cyclodextrin In a vacuum-dried flask, 6-Ot-butyldimethylsilyl-β- 206 mg (0.106 mmol) of cyclodextrin, 1.75 g (13.5 mmol) of diisopropylethylamine (DIPEA) and 5 ml of dichloromethane (DCM) were added and stirred at room temperature to obtain a homogeneous solution. To this was added 0.79 g (9.8 mmol) of chloromethyl methyl ether, and the system was purged with nitrogen, followed by stirring at room temperature for 3 days. When the reaction solution was subjected to TLC analysis (toluene: ethanol = 9: 1), the target product was confirmed at the Rf value of 0.37. The reaction mixture was diluted with 100 mL of MTBE, and this was washed with 50 mL of 1N hydrochloric acid, 50 mL of saturated aqueous sodium hydrogen carbonate solution, and 100 mL of saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and then concentrated to obtain 258 mg of a crude product. This was purified by silica gel chromatography (toluene: ethanol = 93: 7) to obtain 174 mg of the title object compound (yield 64%).

Example 2: Synthesis of 6-Ot-butyldimethylsilyl-2,3-di-O-methoxymethyl-γ-cyclodextrin In Example 1, 6-Ot-butyldimethylsilyl-β-cyclodextrin The title product was obtained in a yield of 66% in the same manner as in Example 1 except that 6-Ot-butyldimethylsilyl-γ-cyclodextrin was used instead of.

Physical property data (NMR spectroscopy / proton, 250 MHz, ppm) 0.02 (s; 48H); 0.87 (s; 72H); 3.36 (dd; J = 2.5 Hz, 8.5 Hz; 8H); 3.39 (s; 24H); 3.44 (s; 24H); 3.64 (d; J = 10.0 Hz; 16H); 3.87 (t; J = 8.5 Hz; 8H); 94 (t; J = 8.5 Hz; 8H); 4.79 (d; J = 6.5 Hz; 8H); 4.82 (d; J = 6.5 Hz; 8H); 4.99 (d; J = 6.5 Hz; 8H); 5.27 (d; J = 2.5 Hz; 8H).
(NMR spectroscopy, carbon 13, 62.5 MHz, ppm) -3.6, -3.2, 20.0, 27.5, 57.0, 57.2, 64.3, 74.0, 78. 6, 79.7, 80.1, 99.5, 100.6.

Example 3 Synthesis of 6-Ot-butyldimethylsilyl-2,3-di-O-ethoxymethyl-γ-cyclodextrin In Example 2, ethoxymethyl chloride was used instead of methoxymethyl chloride, and the reaction was performed. The title product was obtained in a yield of 92% in the same manner as in Example 2 except that the temperature was changed to 60 ° C.

Example 4: Preparation of capillary column for gas chromatography A commercially available fused silica capillary column (inner diameter 0.25 mm) is wound up to about 30 m, the inner surface is activated (2% hydrochloric acid, 240 ° C., 4 hours), and vacuum dried. Then, after inactivation treatment (330 ° C., 10 hours) using hexamethyldisilazane, the inside was washed with toluene and dried with dry nitrogen gas. The silicone diluted liquid phase of the cyclodextrin derivative was applied to the inside of this product based on the static method. That is, 6-Ot-butyldimethylsilyl-2,3-di-O-methoxymethyl-γ-cyclodextrin prepared in Example 2 was added to silicone OV-1701vi so as to be 33% by weight, This was made into a dichloromethane solution (0.4%), this solution was packed inside the column and the end was sealed, and then connected to a vacuum system from the other under a constant temperature condition of 35 ° C., and the solvent was distilled off. To form a uniform liquid phase film. After the application is completed, in order to stabilize the liquid phase, remove residual solvent, etc., and mature the column, the column is attached to a gas chromatography apparatus and treated at 230 ° C. for 5 hours under a hydrogen gas flow. A chiral separation column was obtained.

Comparative Example 1
6-Ot-butyldimethylsilyl-2,3-di-O-acetyl-γ-cyclodextrin having a similar structure conventionally known as a comparison target was synthesized (J. Microcol. Sep. p395-402, 1991). Dry 6-Ot-butyldimethylsilyl-γ-cyclodextrin (188 mg) was dissolved in triethylamine (10 mL), and N, N-dimethylaminopyridine (83 mg) was added and dissolved by stirring. Acetic anhydride (1.39 g) was slowly added thereto, and the mixture was stirred at room temperature for 3 days. Then, water was added to stop the reaction, followed by post-treatment by a conventional method and silica gel column chromatography. -Ot-butyldimethylsilyl-2,3-di-O-acetyl-γ-cyclodextrin was obtained. White powder, yield 149 g (61% yield). The liquid phase thus obtained was applied to a capillary column under the same conditions according to Example 4 to obtain a comparative chiral separation column.

Example 5: Example of Capillary GC Analysis Using the capillary columns prepared in Example 4 and Comparative Example 1, the following measurement samples were separated under the following measurement conditions. The capillary column of Example 4 was measured with the column temperature under the following gas chromatograph measurement conditions constant, and the separation coefficient (α) and resolution (Rs) were determined from the retention coefficient of each compound and the half width of the peak. . The results are shown in Table 1. Furthermore, the gas chromatogram which analyzed each sample with each capillary column is shown in FIGS.

  The α value indicates the ratio of the retention times of the peaks on the enantiomer chromatogram. When the α value is 1.0, the peak is completely overlapped, and the α value is greater than 1.0. The better the separation. The Rs value indicates the shape of the peak on the chromatogram of the enantiomer and the separation width thereof. When the Rs value is smaller than 1.0, the peak is overlapped. The Rs value is 1.0. Complete separation, and the larger the Rs value is, the more the peak is separated.

Sample measurement conditions Apparatus: Carlo Elba Sturmentatazione (Milan) Model 4160
Column: Inner diameter 0.25mm, outer diameter 0.47mm, length 30m
Column temperature: in the range of 40 ° C. to 210 ° C. Carrier gas: Hydrogen gas Carrier gas pressure (at the column inlet): 100 kPa (However, if the holding time is too short at the pressure, measure at 50 kPa. (Notice that individually)
Split ratio: 30: 1
Inlet temperature: 210 ° C
Detector temperature: 220 ° C
Detector: Hydrogen flame ionization detector
Sample to be measured Sample 1: Single compound (3,3,5-trimethylcyclohexanone)
(Measurement condition)
-Column used: capillary column of Example 4-Measurement temperature: 70 ° C
Sample 2: Mixture (A: 3-methyl-2-pentanone; B: acetoin; C: 5-methyl-2-hepten-4-one; D: 3,5-dimethyl-1,2-cyclopentanedione)
(Measurement condition)
Column used: Capillary column of Example 4 Measurement temperature: After sample introduction at 30 ° C., the sample was maintained at the same temperature for 2 minutes, and then heated at a rate of 2 ° C. per minute.
Sample 3: Single compound (2-pentanol)
(Measurement condition)
Column used: capillary column of Example 4 or Comparative Example 1 Measurement temperature: 40 ° C.
Sample 4: Single compound (2-hexanol)
(Measurement condition)
-Column used: capillary column of Example 4 or Comparative Example 1-Measurement temperature: 50 ° C
Sample 5: Single compound (2-methylbutyraldehyde)
(Measurement condition)
Column used: capillary column of Example 4 or Comparative Example 1 Measurement temperature: 40 ° C.
Sample 6: Single compound (3-buten-2-ol)
(Measurement condition)
Column used: capillary column of Example 4 or Comparative Example 1 Measurement temperature: 40 ° C. (carrier gas pressure 50 kPa)
Sample 7: single compound (ethyl 2-methylbutyrate)
(Measurement condition)
Column used: capillary column of Example 4 or Comparative Example 1 Measurement temperature: 40 ° C.

  From the measurement results in Table 1, it can be seen that the capillary column of Example 4 is well separated for a wide range of compounds. Moreover, as shown in FIGS. 1-12, it turns out that the capillary column of Example 4 is excellent in the separation performance of an enantiomer compared with the capillary column of the comparative example 1. FIG.

FIG. 6 is a diagram showing a gas chromatogram obtained by measuring Sample 1 with the capillary column of Example 4. FIG. 6 is a diagram showing a gas chromatogram obtained by measuring sample 2 with the capillary column of Example 4. 4 is a diagram showing a gas chromatogram obtained by measuring a sample 3 with a capillary column of Comparative Example 1. FIG. FIG. 6 is a diagram showing a gas chromatogram obtained by measuring Sample 3 with the capillary column of Example 4. 4 is a diagram showing a gas chromatogram obtained by measuring a sample 4 with a capillary column of Comparative Example 1. FIG. FIG. 6 is a diagram showing a gas chromatogram obtained by measuring Sample 4 with the capillary column of Example 4. 6 is a diagram showing a gas chromatogram obtained by measuring a sample 5 with a capillary column of Comparative Example 1. FIG. FIG. 5 is a diagram showing a gas chromatogram obtained by measuring a sample 5 with the capillary column of Example 4. 6 is a diagram showing a gas chromatogram obtained by measuring a sample 6 with a capillary column of Comparative Example 1. FIG. 6 is a diagram showing a gas chromatogram obtained by measuring a sample 6 with a capillary column of Example 4. FIG. 4 is a diagram showing a gas chromatogram obtained by measuring a sample 7 using a capillary column of Comparative Example 1. FIG. 6 is a diagram showing a gas chromatogram obtained by measuring a sample 7 with a capillary column of Example 4. FIG.

Claims (3)

Following formula (1)
Wherein R ₁ represents a t-butyldimethylsilyl group, a triisopropylsilyl group or a t-butyldiphenylsilyl group, R ₂ represents an optionally substituted alkoxymethyl group, and n represents 6, 7 Or 8)
A substituted cyclodextrin represented by   An optically active column packing material for gas chromatography, comprising the substituted cyclodextrin according to claim 1. Following formula (2)
(Wherein R ₁ and n are as defined in claim 1)
A cyclodextrin derivative represented by the following formula (3)
(Wherein R ₂ has the same meaning as described in claim 1, and X represents a halogen atom)
The following formula (1) characterized by reacting with an alkoxymethyl halide represented by the formula:
(Wherein R ₁ , R ₂ and n are as defined in claim 1).
The manufacturing method of substituted cyclodextrin represented by these.