JPH01319502A - Cyclodextrin derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R1 and R2 are hydroxyl group or formula II (R is H, 1-4C alkyl, etc.), provided that R2 is formula II when R1 is hydroxyl group and R1 is formula II when R2 is hydroxyl group]. EXAMPLE:Mono(2-benzylcarboxy-(S)-methylamino-2-deoxy)-beta-cyclodextrin. USE:Useful for separating, purifying optically active compounds, etc., with ultrahigh high asymmetric discrimination ability. PREPARATION:Cyclodextrin expressed by formula II is initially reacted with p-toluenesulfonyl chloride or m-nitrophenyl-ptoluenesulfonic acid in a DMF/ carbonic acid buffer solution, etc., to provide a compound expressed by formula IV (R3 and R4 are as follows; R3 is H and R4 is toluenesulfonyl or R3 is toluenesulfonyl and R4 is H), which is then preferably reacted with an amino acid expressed by formula V at 30-45 deg.C for 12-36hr.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel cyclodextrin derivative and a method for producing the same, and more particularly to a cyclodextrin derivative having asymmetric discrimination ability and a method for producing the same.

= 4 - [Prior art] Nclodextrin is D-glucobylanose or α-1
, 4 is a cylindrical cyclic compound formed by gelcondo bonds, and the outside of the cylinder of the cyclic compound has many hydroxyl groups and is hydrophilic, but the inside of the cylinder is hydrophobic. This cyclodextrin is known as a host compound in which various organic compounds having a hydrophobic group such as a phenyl group or a naphthyl group are included because the inside of the cylinder is hydrophobic. Furthermore, since cyclodextrin has five optically active carbon atoms per molecule of D-glucobylanose, it is also known as a compound having asymmetric discrimination ability.

In recent years, the importance of separating and purifying optically active compounds has increased, and there has been a growing trend to utilize the asymmetric discrimination ability of cyclodextrins for this purpose. For example, a method for separating and purifying optically active compounds using cyclodextrin supported on silica gel or the like as an adsorption carrier for liquid chromatography, or a method for separating and purifying optically active compounds by adding cyfrobukis I/phosphorus to the mobile phase in liquid chromatography. Methods for separating and purifying compounds are known. However, these methods have insufficient ability to discriminate the chirality of cyclodextrins.

[Invention or problem to be solved]

The object of the present invention is the separation of the optically active compounds.

Overcoming the drawbacks of cyclodextrin used in purification,
The object of the present invention is to provide a cyclodextrin derivative with excellent chiral discrimination ability and a method for producing the same.

[Means to solve the problem]

The present invention provides a cyclodextrin derivative that can achieve the above object and a method for producing the same.

That is, the present invention represents a general formula. Here, R is hydrogen, a lower alkyl group having 1 to 4 carbon atoms and its hydroxyl, amino, carboxyl, carbamoyl, mercapto, methylmercapto or guanidino monosubstituted product, benzyl group, p-hydroxybenzyl group, 3-indolylmethyl group , 4-imidazolylmethyl group. However, when R1 is a hydroxyl group, R2 or 7 is represented.] It relates to a cyclodextrin derivative represented by the following.

The present invention also provides a combination of a cyclodextrin represented by the general formula (III) (hereinafter referred to as blank) [wherein n represents 5, 6 or 7] and p-toluenesulfonyl chloride or m-nitrophenyl-p-toluenesulfonic acid. to form a compound of the general formula (III) (III) [where n represents 5, 6 or 7, and R3゜-8
- Represent. However, when R3 is hydrogen, R4 represents a toluenesulfonyl group, and when R4 is hydrogen, R3 represents a toluenesulfonyl group], and then reacting the compound with an amino acid. (I) represents. Here, R is hydrogen, a lower alkyl group having 1 to 4 carbon atoms and its hydroxyl, amino, carboxyl, carbamoyl, mercapto, methylmercapto or guanidino monosubstituted product, benzyl group, p-hydroquine benzyl group, 3-indolylmethyl group, 4-imidazolylmethyl=10 to 4-imidazolylmethyl group. However, when R is a hydroxyl group, R2 represents or 7.] This invention relates to a method for producing a cyclodextrin derivative represented by the following.

Furthermore, the present invention provides general formula (III) (m) [In the formula, n represents 5, 6 or 7, and Ra.

R4 represents hydrogen or a toluenesulfonyl group. However, when R is hydrogen, R4 is toluenesulfonyl R3 is a toluenesulfonyl group] By reacting thorium iodide with a cyclodextrin derivative represented by the formula (IV) (N) [where n is R5 represents 5, 6 or 7.

R represents a hydroxyl group or iodine. Tatashi, R.

When R is a hydroxyl group, R represents iodine, and when R6 is a hydroxyl group, R5 represents iodine] General formula (1) is characterized by obtaining a compound represented by the following formula, and then reacting the compound with an amino acid. ) represents. Here, R is hydrogen, a lower alkyl group having 1 to 4 carbon atoms and its hydroxyl, amino, carboxyl, carbamoyl, mercapto, methylmercapto or guanidino monosubstituted product, benzyl group, p-hydroxybenzyl group, 3-indolylmethyl group , represents a 4-imidazolylmethyl group. However, when R is a hydroxyl group, R2 represents ■ - 1 3 = -] 2 - or 7.

Hereinafter, the cyclodextrin derivative represented by the general formula (I) and the method for producing the same according to the present invention will be explained.

The cyclodextrin derivative represented by the general formula (I) of the present invention can be produced by an N-alkylation method via a so-called leaving group such as p-toluenesulfonyl group.

When producing the cyclodextrin derivative represented by general formula (1), it can be produced, for example, according to reaction routes A and B shown below. However, R1 and R2 in reaction routes A and B.

R3, R4, R5, R6, n and R are the same as above. Also, the general formula (I) -1, (1) -2
.

(m) -1, (In) -2 and (IV)
-1 represents the general formula (I), (m), (I
Represents a compound in which one of V) has a hydroxyl group.

(Reaction route A) Dimethylformamide/carbonate buffer □> H2N-CH-C0OH (V) (I) -1 In the above reaction route 1-A, compound (m)-1 represented by general formula (III)-1 When obtaining, for example, TeLrahedron Letters (TeLrahedron Letters)
The method can be carried out as described in, for example, Vol. 23, p. 3451 (1,982). That is, m-nitrophenyl- to cyclotextrin (■)
60° in a mixture of carbonate buffer prepared by adding 1 equivalent of p-toluenesulfonic acid, dimethylpolamide, 0.2 mol of sodium carbonate aqueous solution, and 0.2 mol of sodium bicarbonate aqueous solution. It can be obtained by reacting at C for 1 hour. When obtaining the cyclodextrin derivative (I)-1 represented by the general formula (I)-1 from the compound (m)-1 represented by the general formula (III)-1, the general formula (I[I)-1 Compound (III) represented by
-1 in a suitable solvent, such as a 1N aqueous sodium hydroxide solution, pyridine, dimethylformamide, or a potassium hydroxide aqueous solution, and then add the general formula (V
1 to 10 equivalents, preferably 2 to 6 equivalents, of the amino acid (V) represented by ) are added and reacted. The reaction temperature at this time is maintained at 25-55°C, preferably 30-45°C. The appropriate reaction time is 8 to 48 hours, preferably 12 to 36 hours. When the reaction product is worked up by a conventional method, a cyclodextrin derivative represented by the general formula (I)-1 (R2 is -NH-CHR) (1)-1 is obtained.

0OH (blank space below) (Reaction route B) Carbonate buffer NaI/water In the above reaction route B, from the cyclodextrin (n) represented by the general formula (II), the compound (m) represented by the general formula (m)-2 is )-2, Pryten Chemical Society of Japan (Bull
, Chem, Soc, Jpn, ) Volume 53,
As described on page 3221 (1980), etc.
For example, cyclodextrin (II) is dissolved in a carbonate buffer prepared by mixing 0.2 mol of sodium carbonate aqueous solution and 0.2 mol of sodium bicarbonate aqueous solution in a ratio of 9:1, and p-toluenesulfonyl chloride is dissolved in it. It can be obtained by adding 10 equivalents of acetonitrile, heating with soap, and reacting for 1 hour. Compound represented by general formula (III)-2 (Iff
)-2 to obtain the cyclodextrin derivative (I)-2 represented by the general formula (1)-2, the general formula (I)-2 is obtained from the general formula (I)-2.
Compound (m)-2 represented by II)-2 is dissolved in a suitable solvent such as water, and then sodium iodide is dissolved in
The reaction is carried out by adding 6 equivalents, preferably 2 to 3 equivalents. The reaction temperature at this time is 60 to 90°C, preferably 75 to 8°C.
Keep at 5℃. Anti-window time is 05 to 4 hours, preferably 1
~2 hours is appropriate. 1 to 8 equivalents, preferably 2 to 8 equivalents of amino acid (V) represented by general formula (V) are added to this reaction solution.
4 equivalents are added and reacted. The reaction temperature at this time was 60
Maintain at ~90°C, preferably 75-85°C.

The reaction time is suitably 20 to 80 hours, preferably 40 to 60 hours. After the reaction product is worked up in a conventional manner, cyclo(1)-2 of general formula (I)-2 is obtained.

Amino acids used in reaction route A and reaction route B include alanine, glycine, valine, leucine, isoleucine, serine, leonine, lysine, aspartic acid, glutamic acid, cysteine, methionine,
Examples include arginine, phenylalanine, tyrosine, tryptophan, and histidine.

〔Example〕

Hereinafter, the present invention will be explained in more detail with reference to Examples, and it goes without saying that the technical scope of the present invention is not limited to these Examples.

Example] Production of phosphorus β-synchrodextrin 12gm-nitrophenyl-
3.1 g of p-toluenesulfonic acid was dissolved in 120 ml of dimethylformamide, and 0.2 molar carbonate buffer (0.2
A solution of 36 ml of a 0.2 molar sodium bicarbonate aqueous solution added to 36 ml of a molar aqueous sodium carbonate solution was added, and the mixture was stirred at 60°C for 1 hour. After neutralizing the reaction solution with 1N hydrochloric acid, the precipitate was filtered, and 750 ml of acetone was added to the quenched solution. Next, the resulting precipitate was further filtered, and 1250 ml of acetone was added to the quenching solution. The resulting precipitate was filtered and washed with acetone to form a white solid (2-ph).
1 g of luenesulfonyloxy-2-deoxy)-β-cyclodextrin was obtained.

After dissolving 0.26 g of this mono(2-p-toluenesulfonyloquine-2-deoxy)-β-cyclodextrin and 1.3 g of L-phenylalanine O in a 4 molar thorium hydroxide aqueous solution, the solution was heated at 40°C. 2411. Stir for 'j. After neutralizing the reaction solution with 1N hydrochloric acid, acetone 200
ml was added, and the resulting precipitate was filtered. The residue was subjected to liquid chromatography (column: 5hodex■0Hpak)
B-2001,) to produce a pale yellow solid mono (
2-benzylcarboxy-(S)-methylamino-2-
002 g of (deoxy)-β-cyclodextrin was obtained.

Spectral data of mono(2-benzylcarboxy-(S)-methylamino-2-deoxy)-β-cyclodextrin is shown below.

Nuclear magnetic resonance spectrum (D20. Internal standard 1-IJ methylsilylpropanesulfonate) δ: 3.10-3.
30 (2 old winter doublet), 3.40-4.00 (43H, multiplet), 4.96 (7H, doublet), 7.1.8-7.
40 (5N, multiplet) infrared absorption spectrum (KBr)c
m-1: 1.725.3450 (Main items only) Example 2 510 g of α-cyclodextrin was added to 4600 ml of 0.2 M carbonate buffer (0.2 M sodium carbonate aqueous solution).
．． 955 g of p-toluenesulfonyl chloride was dissolved in a small amount of acetonitrile (approx. 4000 ml) at room temperature.
) was added dropwise over 1 hour while stirring. After further stirring at room temperature for 1 hour, the mixture was neutralized with 1N hydrochloric acid and the precipitate was removed. The solution was transferred to an ion exchange resin (Δm
berliteoMB-3) and then liquid chromatography (column 5hodexoOHpakB-5).
001) to obtain 5 g of white solid mono(3-p-toluenesulfonyloxy-3-deoxy)-α-cyclodextrin 1.

115 g of this mono(3-p-t-luenesulfonyloxy-3-deokine)-α-enchodextrin and 30 g of sodium iodide were dissolved in water and stirred at 80° C. for an hour. 4.0 g of D-histidine was added to this reaction solution, and the mixture was further stirred at 80° C. for 48 hours. Next, after distilling off the solvent using an evaporator, liquid chromatography (
The product was purified by column 5hodex 0Hpak B-5001) to obtain 5 g of mono(3-carpoxyimidazol-4-ylmethyl-(R)-methylimino-3-deoxy)-α-cyclodextrin as a pale yellow solid.

Below, mono(3-carboximidazol-4-ylmethyl-(I?)-methylimino-3-deoxy)-α
- Shows spectral data of cyclodextrin.

Nuclear magnetic resonance spectrum (D20, internal standard trimethylsilylpropane sulfonate) δ 3.40-4.1
O (37H, multiplet), 5.40 (5H, doublet).

7.70 (LH, double line) Ultraviolet absorption spectrum λ nm+226aX Representative test examples regarding the chiral discrimination ability of the cyclodextrin derivative of the present invention are shown below.

1 24 - Test Example 1 4.5 g of mono(3-carboximidazol-4-ylmethyl-(R)-methylimino-3-deoxy)-α-cyclodextrin obtained in Example 2 was dissolved in dimethylformamide, and dicyclodextrin was dissolved in dimethylformamide. hexylcarbodiimide 3
．． A terminally aminated gel (hereinafter abbreviated as gel) prepared by reacting 1,3-propanediamine with 1,3-propanediamine was added to an epoxy group-containing gel-like copolymer obtained from 0 g and grindyl methacrylate and ethylene glycol methacrylate, and the mixture was heated overnight in the apparatus. did.

After filtering and washing the reaction solution, the residue was treated with acetic anhydride to obtain 5.0 g of a white solid nclodextrin derivative-supported gel. The adsorption carrier thus obtained has a β content per 1 g of dry gel.
- It was confirmed that 100 μmol of cyclodextrin was carried on the adsorption carrier by converting the cyclodextrin into glucose units with 2N hydrochloric acid and quantifying the resultant by liquid chromatography.

This M-absorbing carrier was packed into a 6.0 mm φ x 250 mm stainless steel column, and dansylphenylalanine was analyzed using high performance liquid chromatography, and the results shown in Table 1 were obtained.

Analysis conditions, eluent: water-methanol (5:5) elution rate: 0.5 ml/min detector: ultraviolet spectrophotometer (254 nm).
ylmethyl-(R)-methylimino-3-deoxy)-
A test was also conducted on a gel that supported unmodified β-cyclodextrin instead of α-cyclodextrin (carrying amount: 82 μmol).

Table 1 Test Example 2 24 g of dansyl-D-phenylalanine was dissolved in 50 ml of dimethylformamide, and 2.5 g of dichlorohexyl tribodiimyl 1' and 2.5 g of dansyl-D-phenylalanine from Test Example 1 were added. Add Og,
- It was installed in the evening. The reaction solution was filtered and washed, and the residue was treated with acetic anhydride to obtain 51 g of Dannru D-phenylalanine-supported gel as a pale yellow solid. The adsorption carrier thus obtained supports 1.1 mmol of dansyl-D-phenylalanine per 1 g of dry gel, which is the difference between the amount of amino groups remaining in the gel before reaction and the amount of amino groups remaining before acetylation. This was confirmed by this.

It was produced in the same manner as the dansyl-D-phenylalanine-supported gel.

When these adsorption carriers were packed in a stainless steel column of 6 mm φ x 250+ nm and analyzed for β-cyclodextrin and its derivatives using a high performance liquid chromatography device, the results shown in Table 2 were obtained.

Analysis conditions, eluent: water-methanol (5:5) Elution rate: 0.5 ml/min Detector = ultraviolet spectrophotometer (254 nm) (blank below) Table 2 Absolute configuration R4, 74, 00, 7 R2 R is benzyl absolute configuration S 4.7 3.7 1. , R of OR2 has methyl absolute configuration R4,74,1,O,O R of R2 has methyl absolute configuration S 4.7 3.9 0.8R of R2
or isopropyl absolute configuration R4,73,90,8 R of R2 is isopropyl absolute configuration S 4.7 3.9 0.8R of R2
is carboxymethyl absolute configuration R4,73,71,0 R2 is carboxymethyl absolute configuration R4,73,80,9 Amino acid R or pencil 4.8 4.8
0α-cyclodextrin 4.6 4
．． 6 0β-Cyclodextrin 4.7
4.7 0 (blank below) -3n - As is clear from Table 2, the cyclodextrin derivatives obtained according to the present invention have the following properties when using Column D and Column L, each carrying an optical isomer: Since the difference in elution volume was wider in both cases compared to unmodified cyclodextrin, it was confirmed that the asymmetric discrimination ability was increased.

〔Effect of the invention〕

As is clear from the test examples, the cyclodextrin derivative of the present invention has extremely high asymmetric discrimination ability compared to unmodified cyclodextrin, and is useful for example in the separation 2 analysis of optically active compounds in high performance liquid chromatography. It is clear that this method will be a powerful means for application to industrial separation and purification equipment.

In addition, the cyclodextrin derivative according to the present invention can be used as a molecular encapsulation material in the fields of food, medicine, cosmetics, etc. to stabilize, solubilize, and nonvolatile substances.

It is expected that it will be used as an antioxidant,
It is also expected to be a model compound for enzymatic reactions.

Claims (2)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) [In the formula, R_1 and R_2 represent hydroxyl groups or ▲There are mathematical formulas, chemical formulas, tables, etc.▼. Here, R is hydrogen, a lower alkyl group having 1 to 4 carbon atoms and its hydroxyl, amino, carboxyl, carbamoyl, mercapto, methylmercapto or guanidino monosubstituted product, benzyl group, p
-Hydroxybenzyl group, 3-indolylmethyl group, 4
- represents an imidazolylmethyl group. However, when R_1 is a hydroxyl group, R_2 has a ▲ mathematical formula, chemical formula, table, etc. ▼
When R_2 is a hydroxyl group, R_1 represents ▲There are mathematical formulas, chemical formulas, tables, etc.▼. n represents 5, 6 or 7] A cyclodextrin derivative represented by: (2) General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) [In the formula, n represents 5, 6 or 7] Cyclodextrin and p-toluenesulfonyl chloride or m-nitrophenyl represented by -By reacting with p-toluenesulfonic acid, the general formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula, n represents 5, 6 or 7, R_3, R_4
represents hydrogen or a toluenesulfonyl group. provided that when R_3 is hydrogen, R_4 represents a toluenesulfonyl group, and when R_4 is hydrogen, R_3 represents a toluenesulfonyl group] and then reacting the compound with an amino acid. Claim (1) A method for producing the described cyclodextrin derivative. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula, n represents 5, 6 or 7, R_3, R_4
represents hydrogen or a toluenesulfonyl group. However, when R_3 is hydrogen, R_4 represents a toluenesulfonyl group, and when R_4 is hydrogen, R_3 represents a toluenesulfonyl group] A cyclodextrin derivative represented by the following is reacted with sodium iodide to form the general formula (IV) ▲ Formula, There are chemical formulas, tables, etc. ▼ (IV) [In the formula, n represents 5, 6 or 7, R_5, R_6
represents a hydroxyl group and iodine. However, when R_5 is a hydroxyl group, R_6 represents iodine, and when R_6 is a hydroxyl group, R_6 represents iodine.
_5 represents iodine] The method for producing a cyclodextrin derivative according to claim (1), comprising obtaining a compound represented by the following and then reacting the compound with an amino acid.