JP2843128B2 - Novel cyclodextrin derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a surfactant having both surface activity and inclusion ability, and a stabilizer, sustained release agent or carrier for pharmaceuticals, fragrances, dyes and the like. TECHNICAL FIELD The present invention relates to a novel cyclodextrin derivative useful as, for example, and a production method thereof.

[Problems to be solved by conventional technology and invention]

Cyclodextrin, a cyclic oligosaccharide in which glucose is α-1,4 linked, has α in which 6 glucoses are linked.
-Cyclodextrin (cyclohexamylose), 7
Β-cyclodextrin (cycloheptaamylose) to which eight glucoses are bound, and γ-cyclodextrin (cyclooctaamylose) to which eight glucoses are bound are generally known.

Cyclodextrin has the property of enclosing a fat-soluble substance (guest compound) in its hydrophobic cavity, and this phenomenon is used to make volatile substances nonvolatile and sustained release, and to stabilize unstable substances. It is widely used in foods, cosmetics, toiletry products, pharmaceuticals, etc. for the purpose of solubilization or solubilization of hardly soluble substances. However, cyclodextrins, especially β-cyclodextrins, which are the easiest to manufacture and are inexpensive, have problems such as low solubility in water, and inclusion products of cyclodextrins being hardly soluble and causing precipitation. However, there is a drawback that the concentration used is limited. Further, when cyclodextrin is used in a detergent composition such as a shampoo and a detergent in the presence of a surfactant,
In some applications, the inclusion of the target guest compound molecule and the surfactant molecule occurs in competition, or the inclusion of the surfactant molecule occurs preferentially and does not function sufficiently as an inclusion body. There were very serious restrictions.

Attempts have been made to solve the above-mentioned solubility problem by chemically modifying cyclodextrin. For example, JP-A-57-4914, JP-A-61-200101
JP-A-62-59601 and JP-A-63-41505 describe partial methylation, U.S. Pat.
JP-197602, JP-A-63-27440 and JP-A-63-46201 attempt addition and branching of saccharides such as glucose and mannose to improve the solubility in water. Have been. However, in these cyclodextrin derivatives, the inclusion ability in the presence of a surfactant is not improved at all in comparison with the cyclodextrin as a raw material, and the inclusion ability when used in a detergent composition is not improved. No improvement effect has been seen for the decrease in

[Means for solving the problem]

In view of the above-described circumstances, the present inventors have conducted intensive studies on the expression of novel excellent properties by chemical modification of cyclodextrin or branched cyclodextrin having a sugar residue as a side chain, and as a result, cyclodextrin or sugar residue A surface-active cyclodextrin derivative obtained by introducing a long-chain alkyl group or a long-chain alkenyl group into a branched cyclodextrin having a side chain, and a hydrophilic group to impart surface activity, more specifically, a cyclodextrin or a sugar residue. The present invention has been found that a long-chain alkyl or alkenyl succinic acid half-ester metal salt of a branched cyclodextrin having a side chain of 1 is extremely excellent in water solubility and inclusion ability of a guest compound in the presence of a surfactant. Was completed.

That is, the present invention provides a novel surfactant cyclodextrin derivative represented by the following general formula (I) and a method for producing the same.

CD- _Bn (I) [where CD: cyclodextrin, which is a cyclic oligosaccharide having six or more α-1,4 linked glucoses, or a branched cyclodextrin having a sugar residue as a side chain (hereinafter, cyclodextrin) (Abbreviated as) and shows the cyclic oligosaccharide residues remaining after removing the hydrogen atoms of all non-glycosidic hydroxyl groups.

n: Indicates the number of non-glycosidic hydroxyl groups in cyclodextrins.

B: a group in which hydrogen atoms of all non-glycosidic hydroxyl groups of cyclodextrins are bonded to an oxygen atom which has been bonded, a hydrogen atom or Is shown. However, at least one of the n B groups is It is. Here, M is a hydrogen atom, an alkali metal, an alkaline earth metal, ammonium, a mono-, di- or trialkanol ammonium having 2 to 3 carbon atoms, an alkyl- or alkenyl-substituted ammonium having 1 to 18 carbon atoms, an alkyl-substituted pyridinium, Or indicates a basic amino acid,
A is Or a mixture thereof, and R represents an alkyl or alkenyl group having 6 to 20 carbon atoms. Among the cyclodextrin derivatives represented by the general formula (I), those in which the cyclic oligosaccharide residue CD is a β-cyclodextrin residue and R is an alkenyl group having 6 to 20 carbon atoms are particularly preferable. Specific examples of the groups represented by, CD and B are as follows.

Conventional examples of the synthesis of half-ester carboxylic acids by the reaction of cyclodextrin with a cyclic acid anhydride include US Pat.
Synthesis of cyclodextrin half-ester carboxylic acid having an average degree of substitution of 7 by reaction of maleic anhydride or phthalic anhydride with cyclodextrin described in No. 3260 is known, but these have almost no surface activity, It was intended for use as a polymeric plasticizer.

The surface-active cyclodextrin derivative of the present invention represented by the general formula (I) is a novel substance and has excellent inclusion ability and surface-activity, and the above-mentioned cyclodextrin having no surface activity. Derivatives (JP-A-63-4150
No. 5, U.S. Pat.No. 3,457,973, JP-A-63-46201, U.S. Pat.
No. 0).

The surface active cyclodextrin derivative represented by the general formula (I) (hereinafter, abbreviated as surface active cyclodextrin derivative (I)) provided by the present invention is obtained by converting cyclodextrins to alkenyl succinic anhydride or alkyl succinic anhydride. It is obtained by reacting with a substance and, if necessary, neutralizing with an alkaline substance.

The present inventors have conducted intensive studies on the method for synthesizing the above-mentioned surfactant cyclodextrin derivative (I). As a result, cyclodextrins and alkenyl succinic anhydrides or alkyl succinic anhydrides were obtained in a solvent containing no water and no alcohol. Was reacted preferably in the presence of an alkaline substance to obtain the corresponding surface-active cyclodextrin derivative (I) in good yield, and completed the production method of the present invention.

 This reaction is specifically illustrated as follows.

(B group has 7 of 21 B groups. Or a mixture thereof, and the remaining 14 are hydrogen atoms. M has the above-mentioned meaning. In the reaction of the present invention, first, as a solvent, an organic solvent not containing water and alcohol, for example, dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoric triamide (HMPA), dioxane,
Toluene, xylene and the like can be used, but DMF and DMSO in which the raw material cyclodextrins are soluble are desirable. As the alkaline substance, pyridine, triethylamine, caustic potash, caustic soda, and the like can be used, and pyridine and triethylamine are preferable from the viewpoint of solubility in a solvent. In addition, the reaction can be performed in the absence of an alkaline substance, but the progress of the reaction is slow, so the reaction temperature must be extremely high or the reaction time must be increased, and as a result, the reaction reagent is used. Since a side reaction such as formation of a diester in which both carbonyl groups of alkenyl succinic anhydride or alkyl succinic anhydride are esterified easily proceeds, it is preferable to use an alkaline substance. The amount of the alkenyl succinic anhydride or alkyl succinic anhydride as a reaction reagent or the mixture thereof can be arbitrarily selected according to the desired degree of ester substitution of the surface-active cyclodextrin derivative (I). .

The reaction temperature is 0 to 250 ° C, preferably 50 to 150 ° C.
If the temperature exceeds 150 ° C., side reactions such as formation of diester become remarkable, which is not preferable. Although the reaction time depends on the reaction temperature and the amount of the alkaline substance added, 1 to 100 hours is sufficient.

The amount of the alkaline substance to be added may be about 0.1 to 2.0 times, more preferably 1.0 to 1.5 times, by mole ratio, relative to the reaction reagent alkenyl succinic anhydride or alkyl succinic anhydride or a mixture thereof. .

As described above, the amount of the solvent, the alkaline substance and the alkyl succinic anhydride or alkenyl succinic anhydride, or the mixture thereof, the reaction time, the reaction temperature, and the like are arbitrarily set, whereby the surfactant having a desired degree of ester substitution is obtained. The cyclodextrin derivative (I) can be produced. The surfactant cyclodextrin derivative (I) thus obtained is a carboxylic acid type or an alkali neutralized salt type or a mixture thereof depending on the amount of the alkaline substance to be added. It can be used as a complete alkali neutralized salt, or by adding an acidic substance to a complete carboxylic acid form, or further adding an alkaline substance to the carboxylic acid form to use as another alkali neutralized salt ( Neutralization / counter ion exchange step).

The alkaline substance used in the neutralization / counter ion exchange step is an inorganic alkali such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, or monoethanol. Examples include amines, diethanolamine, triethanolamine, decylamine, dodecylamine, basic amino acids, and the like, and these can also be used as aqueous solutions. Further, as the acidic substance, hydrochloric acid, sulfuric acid, formic acid, acetic acid, propionic acid and the like can be used, and it can also be used as an aqueous solution. Neutralization / counter ion exchange is carried out with the above alkaline substance or acidic substance or an aqueous solution thereof at a temperature of 70 ° C. or less for about 1
Stirring for about an hour is sufficient.

The solvent present in the thus-obtained mixture containing the surface active cyclodextrin derivative (I) is first distilled off by heating under reduced pressure (desolvation step), and the remaining inorganic and organic salts are removed. Can be removed by electrodialysis, adsorption with an ion exchange resin, an adsorbent, etc., or solvent purification, recrystallization, etc. (desalting step), but depending on the application, the above neutralization / counter ion exchange step, desolvation step Alternatively, the desalting step can be omitted.

〔The invention's effect〕

The surface-active cyclodextrin (I) of the present invention obtained as described above has a high water solubility in the form of an alkali neutralized salt, and is much higher than cyclodextrins conventionally used in the presence of an activator. Since it has a high inclusion ability, it can be widely used as a masking agent or a sustained release agent for perfume in a detergent composition.

〔Example〕

Hereinafter, the present invention will be described specifically with reference to Examples.
The present invention is not limited by these examples.

Example 1 42.5 g (37.5 mmol) of β-cyclodextrin, anhydrous n
-75.0 g (315 mmol) of decenyl succinic acid and 300 ml of DMF were stirred in a flask at 110 ° C for 17 hours. Then 60 ° C
Then, 174 ml of a 10% -NaOH aqueous solution (containing 17.4 g (435 mmol) of NaOH) was added dropwise in about 30 minutes, and then stirred at 60 ° C. for 30 minutes to obtain a Na salt. Water and DMF were distilled off from the reaction mixture by heating under reduced pressure using an evaporator. The residue was dissolved in 500 ml of methanol, the insoluble precipitate was removed by filtration, the filtrate was concentrated by evaporator, 1 acetone was added, and the resulting white precipitate was collected by filtration and dried to obtain 35.9 g of a white powder. (31.8% yield).

The resulting β-cyclodextrin decenyl succinic acid half ester Na salt has a hydroxyl value of 362.0 and a saponification value of 932,
The iodine value was 56.3.

IR (cm ^-1 , KBr tablet) 3406 (OH), 2926 and 2854 (CH), 1731 (ester carbonyl), 1575 and 1407 (CO ₂ Na) ¹ H-NMR (δ, ppm) in D ₂ O 0.8 (t) 17.4H; 1.2 (m) 56.3H; 1.9 to 2.8 (m) 40.4H; ,, 3.4 to 4.0 (m) 42.0H; ,,, 5.0 (d) 7.0H; 5.4 (m) 10.7H ;、 From the above results, it was found that the average degree of ester substitution was about 5. This result was in good agreement with the hydroxyl value, saponification value and iodine value.

Example 2 42.5 g (37.5 mmol) of β-cyclodextrin, anhydrous n
-75.0 g (315 mmol) of decenyl succinic acid, 24.9 g of pyridine
(315 mmol) and 300 ml of DMF in a flask at 90 ° C. for 24 hours.
Stirred for hours. Thereafter, the mixture was cooled to 60 ° C., and 147 ml of a 10% -NaOH aqueous solution (containing 14.7 g (368 mmol) of NaOH) was added dropwise in about 30 minutes, and then stirred at 60 ° C. for 30 minutes to obtain a Na salt. The reaction mixture was desolvated, purified by solvent and dried in the same manner as in Example 1 to obtain 89.3 g of β-cyclodextrin decenylsuccinic acid half ester sodium salt (white powder) (yield: 80.6%).

The hydroxyl value of the obtained product was 252.2, the saponification value was 135.6,
The iodine value was 54.7. ¹ H-NMR (δ, ppm) in D ₂ O 0.8 (t) 24.9 H; 1.2 (m) 77.8 H; 1.9 to 2.8 (m) 46.7 H; ,,, 3.4 to 4.0 (m) 42.0 H; ,, , 5.0 (d) 7.0H; 5.4 (m) 10.7H ;, From the above results, it was found that the average degree of ester substitution was about 7.

Example 3 The carboxylic acid type half ester of β-cyclodextrin decenyl succinic acid half ester sodium salt (average degree of substitution about 7) obtained in Example 2, that is, β-cyclodextrin decenyl succinic acid half ester was prepared as follows. Was synthesized as described above.

10.0 g of sodium salt type half ester was dissolved in 100 ml of water, and the pH was adjusted to 4 by dropwise addition of 1N hydrochloric acid. The resulting white precipitate was collected by filtration, washed with a large amount of water until the pH of the filtrate became neutral, and then dried under reduced pressure at 60 ° C for 12 hours to obtain a white powder.
9.1 g were obtained.

The average molecular weight of the obtained product was measured by the VPO method and found to be 2970, and the average degree of ester substitution was 7.7. In addition, the results of elemental analysis agreed well as shown below.

Elemental analysis: C _149.8 H _239.4 O _58.1 (as ester substitution degree 7.7) C H O analysis value (%) 58.22 8.22 32.36 Calculated value (%) 60.59 8.07 31.34 Example 4 Maltosyl α-cyclodextrin 10 g (7.7 mmol),
14.7 g (61.7 mmol) of n-decenyl succinic anhydride, 4.9 g (61.7 mmol) of pyridine and 100 ml of DMF were added to a 300 ml flask in a 9 ml flask.
Stirred at 0 ° C. for 10 hours. Then cool to room temperature, 10%
Sodium hydroxide aqueous solution 24.7ml (sodium hydroxide 61.7ml
mmol), and thereafter the solvent was removed in the same manner as in Example 1.
Solvent purification and further drying gave 18.7 g of maltosyl α-cyclodextrin decenylsuccinic acid half ester sodium salt (white powder) (yield 77.9%).

The obtained product had a hydroxyl value of 262.1 and a saponification value of 118.6.

The sodium salt obtained as described above was neutralized in the same manner as in Example 3 to obtain a carboxylic acid type. The average molecular weight w was 2951 (by the VPO method), and the average degree of ester substitution was about 7. Also, the results of elemental analysis were in good agreement as shown below.

Elemental analysis: C ₁₄₆ H ₂₃₄ O ₆₁ (as an ester degree of substitution 7.0) C H O analysis (%) 58.29 7.92 33.17 Calculated (%) 59.15 7.90 32.95 synthesized β- cyclodextrin decenyl Test Example Example 2 The inclusion ability of succinic acid half ester Na salt (average degree of ester substitution of about 7) with N-phenyl-1-naphthylamine (PNA; guest compound) was measured by fluorescence analysis in an aqueous solution.

For comparison, β conventionally used as an inclusion compound
The inclusion ability of cyclodextrin was also measured.

Measurement conditions: Excitation wavelength 365 nm pH 6.05 25 ° C. 0.05 M-MES buffer PNA (guest compound) concentration 2 × 10 ⁻⁴ mol / β-cyclodextrin decenyl succinic acid half ester Na salt or β-cyclodextrin (host compound) )
Concentration 1 × 10 ^-2 mol / Fig. 1 shows their fluorescence spectra. The higher the PNA fluorescence intensity, the higher the inclusion ability of the guest compound.

As a result, when the β-cyclodextrin derivative synthesized in Example 2 was used as the host compound, the fluorescence intensity was increased as compared with the case where β-cyclodextrin was used as the host compound, and the compound was a guest compound. PNA
It can be seen that the clathrate ability of is increased.

[Brief description of the drawings]

FIG. 1 shows the inclusion ability of β-cyclodextrin decenylsuccinic acid half ester Na salt (average degree of ester substitution about 7) and β-cyclodextrin with N-phenyl-1-naphthylamine (PNA) in aqueous solution. It is a figure showing the result measured by analysis.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ identification symbol FI // C11D 3/22 C11D 3/22 (58) Field surveyed (Int. Cl. ⁶ , DB name) C08B 37/16 A61K 47 / 40

Claims (3)

(57) [Claims] 1. A surfactant cyclodextrin derivative represented by the formula (I). CD- _Bn (I) [where CD: cyclodextrin, which is a cyclic oligosaccharide having six or more α-1,4 linked glucoses, or a branched cyclodextrin having a sugar residue as a side chain (hereinafter, cyclodextrin) (Abbreviated as) and shows the cyclic oligosaccharide residues remaining after removing the hydrogen atoms of all non-glycosidic hydroxyl groups. n: Indicates the number of non-glycosidic hydroxyl groups in cyclodextrins. B: a group in which hydrogen atoms of all non-glycosidic hydroxyl groups of cyclodextrins are bonded to an oxygen atom which has been bonded, a hydrogen atom or Is shown. However, at least one of the n B groups is It is. Here, M is a hydrogen atom, an alkali metal, an alkaline earth metal, ammonium, a mono-, di- or trialkanol ammonium having 2 to 3 carbon atoms, an alkyl or alkenyl-substituted ammonium having 1 to 18 carbon atoms, an alkyl-substituted pyridinium, Or indicates a basic amino acid,
A is Or a mixture thereof, and R represents an alkyl or alkenyl group having 6 to 20 carbon atoms. ] (2) a cyclic oligosaccharide residue represented by the general formula (I):
CD is a β-cyclodextrin residue, and R is 6 carbon atoms.
The cyclodextrin derivative according to claim 1, which is an alkenyl group of from 20 to 20. 3. The method according to claim 1, wherein the cyclodextrin is reacted with an alkenyl succinic anhydride or an alkyl succinic anhydride in a solvent free of water and alcohol. A method for producing the indicated cyclodextrin derivative.