JPH02229832A - Method for producing granular porous chitosan derivative having sulfone group - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a method for producing a granular porous chitosan derivative having a sulfone group, and provides a granular porous chitosan derivative suitable for use in ion exchange resins, chromatographic carriers, etc. K Conventional technology
H. L, Wolforn) et al. (J. AIN.
Chera. Soc. , 81, t764 (1958)
), N,0- Sulfonated products are obtained. Also, Nagasawa et al. (Chen. Phar
n. Bull I. , 20, 157 (1972
) ) describes the N-sulfonation using a sulfuric acid, as described in Japanese Patent Application Laid-Open No. 1986-
No. 203132 discloses obtaining a 0-sulfonated product of the hydroxyl group at the C-6 position of β-D-(1→4) monoglucosamine subunit by a mixed process with sulfuric acid and chlorine sulfonic acid. Regarding granular porous chitosan derivatives, JP-A-63-274457 discloses crosslinking with hexamethylene diisocyanate or the like, followed by N,0-sulfonation with chlorosulfonic acid in pyridine. However, according to such conventional methods, sulfonation of flaky or powdered chitosan increases its hydrophilicity;
It is soluble in water and is unsuitable for use as a finger body. Furthermore, in the sulfonated granular porous chitosan derivative disclosed in JP-A No. 63-274457, crosslinking is performed.
As the amount of sulfonic group introduction increases, the carrier deteriorates, and it has not been possible to obtain a carrier with good performance that has the desired high strength and high sulfonic group introduction rate. The problem that the κ invention attempts to solve] Ki1 San is! Since it is soluble in aqueous solutions such as lilic acid, acetic acid, and dichloroacetic acid, it cannot be used as a carrier in a low OH range, and the range in which it can be stably used is narrow. Furthermore, when flaky or powdered chitosan is sulfonated, its hydrophilicity increases, so it has been impossible to obtain a water-insoluble sulfonated product that can be used as a carrier unless the number of sulfone groups introduced is extremely reduced. In the sulfonation of a granular porous chitosan derivative disclosed in JP-A No. 63-274457, stability in the entire OH region cannot be obtained because crosslinking is performed using a crosslinking agent such as hexamethylene diisocyanate 1. However, as the number of sulfone groups introduced increased, water solubility increased and strength deteriorated due to this, and as the number of sulfone groups introduced increased, the strength increased.
- There was a drawback that the sun derivative dissolved in water, making it difficult to maintain the granularity. In addition, since the sulfonating agent used in this method, chlorosulfonic acid, is highly reactive, it is extremely difficult to obtain a carrier with the desired sulfonic group-introduced structure, and at the same time, it has the disadvantage of poor reproducibility. . Furthermore, the conditions for introducing sulfonic groups are relatively high temperature (
Because the reaction is carried out for a long time at 100℃), the carrier tends to deteriorate, and a considerable proportion of the amino groups in chitosan remain even after the introduction of sulfone groups, resulting in non-specific adsorption when used as a corner ion exchanger. There were other problems. The present invention solves the above-mentioned drawbacks and makes it possible to easily obtain a granular porous chitosan derivative that is stable in the entire pH range, has high strength, and has a desired sulfone group and is suitable for ion exchange resins and chromatography carriers. It was done for a purpose. [1,000 Steps to Solve the Problem] The present invention is a granular porous chitosan prepared by dissolving low molecular weight chitosan in an acidic aqueous solution and dropping the solution into a basic solution to solidify it.
- acetylated with acetic anhydride, crosslinked with diJ-boxy, and then sulfonated with N,N'-dimethylformamide sulfur trioxide complex in N,N''-dimethylformamide. This is a method for producing a granular porous chitosan derivative having a sulfone group.The granular porous chitosan of the present invention has an average molecular weight of io, oo
Low-molecular chitosan having a molecular weight of 0 to 230,000 is used. This low-molecular-weight chitosan was mixed with acetic acid and dichloroacetic acid. It is adjusted to a 2 to 10% aqueous solution by dissolving it in ti acid or the like alone or in a mixture. The chitosan aqueous solution was mixed with sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
When dropped under pressure through a nozzle with a hole diameter of 0.15 m into a basic aqueous solution containing an alkaline substance such as ammonia and ethylenediamine, it solidifies and regenerates into granules. The obtained granules are thoroughly washed with water to obtain granular porous Ki-san. Incidentally, it is also possible to use alcohols such as methanol and ethanol together in the basic aqueous solution. In order to acetylate the granular porous chlorine obtained as described above, it is reacted with acetic anhydride to achieve a degree of deacetylation of 10% or less, preferably 5% or less. The organic solvent for acetylation may be any inert solvent that is inert to acetic anhydride and the reaction product and does not have any effect on the acetylation reaction, such as N,N'-dimethylformamide. , dimethylace1 amide, benzene,
1,4-dioxane, methanol, ethanol, n-butanol, etc. can be used alone or in combination. Note that if the degree of deacetylation exceeds 10%, many free amino groups will remain after sulfonation, which may cause non-specific absorption problems when used as a cation exchange resin. It is desirable that the degree of deacetylation is 10% or less, preferably 5% or less. The thus obtained granular porous chitosan with a degree of deacetylation of 10% or less is deacetylated using dieboxy such as shrimp chlorohydrin, ethylene glycol diglycidyl ether, and polyethylene glycol diglycidyl ether as a crosslinking agent. A method of reacting with the hydroxyl groups of the granular porous Ki-san is used. In addition, hexamethylene diisocyanate, diphenylmethane-4,4゛-
There is a method of using diisocyanate-1, dicarboxylic acid halide, etc., but it is chemically very stable because it is crosslinked by Edel bond, a carrier with extremely high strength can be obtained after crosslinking, and the crosslinking method From the viewpoint of convenience, it is optimal to use dieboxyl compounds such as ethylene glycol diglycidyl ether, polyethylene glycol diglycidyl ether, and polyethylene glycol diglycidyl ether. On the other hand, as the sulfonating agent, an N,N'-dimethylformamide sulfur trioxide complex obtained by dropping sulfur trioxide into N,N'-dimethylformamide is used. Other methods include using chlorosulfonic acid in lysine, using chlorosulfonic acid in dichloroethane, using N,N'-dimethylaniline-sulfuric anhydride complex, and using a mixture of sulfurous anhydride and flii acid anhydride. A method using a mixture of sulfuric acid and chlorosulfonic acid is considered, but the sulfonating agent can be stored stably for a long period of time, the sulfonate suspension can be easily adjusted, and the carrier of the specified introduction suspension can be used. The most preferred method is to use an N,N'-dimethylformamide sulfur trioxide complex because it can be obtained with good reproducibility, the reaction conditions are mild, and the reaction proceeds quickly at room temperature. In this case, by adding the N,N'-dimethylformamide sulfur monotrioxide complex, the reaction temperature at which a desired sulfone group can be introduced as necessary is 20 to 60°C.
℃, and in order to suppress deterioration of the carrier, it is preferable to carry out the reaction at 40°C or lower. Reaction time depends on reaction temperature
It is arbitrarily selected within the range of 1 hour to 12 hours. After the reaction is completed, the sulfonated particulate porous chitosan derivative is neutralized with 1N sodium hydroxide solution and thoroughly washed with water to obtain a particulate porous chitosan derivative having a sulfone group.

【Example】

Hereinafter, the present invention will be explained in detail with reference to examples, but the present invention is not limited to the scope described in the practical examples. Also,
The cation exchange medium (neutral salt decomposition ability) of the granular porous chitosan derivative having a sulfone group, the viscosity of the chitosan acetic acid aqueous solution, and the apparent elastic modulus were determined as follows. Cation exchange capacity〉 Fill the column with a sample whose swelling volume has been accurately measured in advance.
Pour approximately 1N nitric acid at SV50. pH of effluent with pure water
Fluid is passed at SV 100 until the temperature does not indicate medium 4, and then approximately 1H aqueous sodium chloride solution is passed at SV 50. At this time, measure the effluent to an accuracy of 1°C using a volumetric flask. Of this, 50d was titrated with 1/10 14 sodium monohydroxide using phenolphthalein as an indicator, and the cation exchange capacity (CTV) was determined from the following formula. ■ a: 1/10 N sodium hydroxide solution required to neutralize 50 test liquids (d> f: Titer of 1/10 N sodium hydroxide solution V:
Wet viscosity of sample (1) Measured at 20°C using a rotating cylindrical viscometer. Designed elastic modulus> Diameter 3.51 tJt. using rheometer NRl4-2010J-CM (manufactured by Fudo Kogyo Co., Ltd.). depth 2fl
Fill the hole with the sample from which water has been removed on a filter paper, and make a diameter of 3.08 mm.
The compressive stress curve was obtained by compressing the material with a cylindrical rod at a speed of 2 cm/Ilin, and from the slope of the tangent at the 10% deformation point. Example 1. 65 g of chitosan with a degree of deacetylation of 78% was dissolved in 935 g of a 3.25% acetic acid aqueous solution. The viscosity at this time is Get2.
300CI). The solution was dropped into a mixed solution consisting of 6% sodium hydroxide, 20% ethanol, and 74% water through a nozzle with a hole diameter of 0.15 aφ, and the chitosan was coagulated and regenerated into granules, and then heated until it became neutral. Washed with water, average particle size 0. Granular porous chitosan with a diameter of 3rmφ was obtained at 0.8°C. 100 d of this granular porous chitosan (wet state) was reacted with 12.4 g of acetic anhydride in ethanol at room temperature for 24 hours, and then treated with a 1-tOH aqueous solution for 1 hour to form a granular porous chitosan with a degree of deacetylation of 5%. The thus obtained granular porous chitosan (80d) with a degree of deacetylation of 5% (in a wet state) was washed with 1,4-dioxane and mixed with 1.5 g of shrimp chlorohydrin 8d in 1N solution. After adding an aqueous potassium hydroxide solution and reacting at room temperature for 16 hours, the reaction was further carried out at 80°C for 1 hour to cause crosslinking.After washing with water, N,N'
-Cleaned with dimethylformamide 412N,N'-N with 80g of sulfur trioxide added to 1λ of dimethylformamide
, N'-dimethylformamide sulfur monotrioxide complex 1
N,N'-dimethylformamide solution 8G containing 8d,
d was added and reacted at room temperature for 4 hours to perform N,0-sulfonation. After the reaction was completed, the mixture was neutralized with a 1N aqueous sodium hydroxide solution while cooling and thoroughly washed with water to obtain a granular porous chitosan derivative 46d having a sulfone group. The cation exchange content of this product was 80.0 μeq/d, and the elastic modulus of Mika Gt was 3.2xlO6dyn/ci.゜Here, the amount of N,N'-dimethylformamide sulfur trioxide complex added during sulfonation was changed from 18d to 20d,
Three samples were obtained by the same operation. When the cation exchange capacity of each of the three samples was measured, it was found to be 105.0 μe.
q/d. 100.8ueQ/d, 102. θtle
Q/d! It was clear that granular porous chitosan having sulfone groups could be obtained with extremely good reproducibility. The obtained granular porous chitosan containing a total of four types of sulfone was mixed with 0. Even when suspended in an IN'flF acid aqueous solution and a 0.1N sodium hydroxide aqueous solution, it did not dissolve at all, and was a granular porous chitosan derivative having a sulfonic group that was stable in the entire pHia range. Example 2. Granular porous chitosan with an estimated degree of acetylation of 5% was obtained in the same manner as in Example 1, and its 50-《wet state》 was washed with 1,4-dioxane, and 1.769 ethylene glycol diglycidyl ether, 5d of After adding 1N potassium monohydroxide solution and reacting at room temperature for 16 hours, the mixture was further heated to 80°C for 1
The mixture was reacted for a period of time to cause crosslinking. After washing with water, wash with κ,N゜-dimethylformamide and N,N'-dimethylformamide 1.
N,N' containing 10 H,N'-dimethylformamide sulfur trioxide complexes with 80g of sulfur trioxide added to λ
-Dimethylformamide solution 50711! was added and reacted at room temperature for 4 hours to perform N,0-sulfonation. After the reaction was completed, the mixture was neutralized with a 1N aqueous sodium monohydroxide solution while cooling and thoroughly washed with water to obtain a granular porous chitosan derivative 27-1 having a sulfone group. The maximum cation exchange capacity of this product is 120. 5μeQ/d. l'Gt's elastic modulus C3.
OxlO6dyn/cd. Further, even when this granular porous chitosan having a sulfone group was suspended in a 0.1N aqueous acid solution and a 0.1N aqueous sodium hydroxide solution, it did not dissolve and was a stable carrier in the entire pH range. In addition, the N,N'-
Dimethylformamide sulfur monotrioxide complex bond, 4d
, ard, 8d, 12d, and 16d were sulfonated, and the cation exchange content of the obtained granular porous chitosan derivatives having sulfone groups was 29.2 μeQ/d. 71.3μeq/d, 1
51.0μeq/d, 228.9μeq/d
, 310.0 μeq/d, and their apparent elastic moduli are 3. Ox 106den/cal, 3
．． Ox 106dyn/CIK, 2.8x 106
dVn/ci, 2. 7x 106dyn/d
, 2.6x 106dyn/m. FIG. 1 shows the relationship between the amount of the N,N'-dimethylformamide-EM sulfur complex added and the cation exchange capacity of the obtained granular porous chitosan derivative. This shows that the amount of sulfonate groups introduced can be changed arbitrarily by changing the amount of the sulfonating agent, and in addition, it was found that the strength of the carrier did not decrease significantly even when a high amount of sulfonate groups were introduced. . Comparative example 1. Granular porous chitosan 50 obtained in the same manner as in Example 1
ad! (in a wet state) was added 2.19 hexamethylene diisocyanate and reacted in N,N'-dimethylformamide at room temperature for 1 hour. Crosslinked. After washing with N,N'-dimethylformamide, it was washed with anhydrous pyridine. To this, 3.40 d of each was added to 120 d of ice-cooled anhydrous pyridine.
．． Add a solution containing a pyridine-chlorosulfonic acid complex to which chlorosulfonic acid of 3.25 1d, 4.55- is added dropwise, and boil it! ! N,0-sulfonation was performed by reacting in an S bath for 1 hour. After the reaction is complete, add 1N sodium hydroxide 5
00me was added and washed with ethanol to obtain granular porous chitosan having sulfone groups. The cation exchange capacity of this material is 28.8μeQ/
d. 72.6μeQ/n, 150μeQ/d, and apparent elastic modulus are 1.3x 106dyn/c, respectively! ! ，
1.3x 106dyn/cm, 10x10
The shoulder was 6 dyn/c. That is, as shown in Example 2, the granular porous chitosan derivative having sulfonyl groups produced by the method of the present invention has 2.3 to 2.8 times higher strength than that obtained in Comparative Example 1. The thing is clear. Comparative example 2. In the sulfonation method shown in Comparative Example 1, anhydrous pyridine 1
20th! Chlorsulfone added to [i = 3 m,
3.51! , 4d, and 4.5d were used for sulfonation, and the cation exchange capacities of the obtained products were 26.5μeq/rd, OμeQ/me, and OμeQ/me, respectively.
92.5μeq/rd! ．． , 96.2μec+/r
d, and the results are shown in Figure 2. In addition, three samples were obtained in the same manner by changing the chlorsulfonic acid concentration to 5-. This cation exchange conflict is 180. Oaeq/td,
The reproducibility was 65.3 μeq/m and 98.2 μeq/d, and the reproducibility was poor. As a result, it is clear that in the sulfonation method of Comparative Example 1, even if the sulfonation Φ is changed, it is not easy to obtain a porous particulate xyl-san derivative exhibiting desired cation exchange. Effects of the Invention The granular porous chitosan derivative having sulfone groups obtained by the present invention is stable in the entire pH range, and has ion exchange*mi. It has strong strength and is suitable as a carrier for chromatography. As is clear from the description of Examples and Comparative Examples, the granular porous chitosan derivative having a sulfone group of the present invention is not only more stable over the entire pH range than those obtained by conventional sulfonation methods. , it has 2 to 3 times the strength performance. Furthermore, in the method of the present invention, by changing the amount of the sulfonating agent used, the amount of sulfonate introduced can be adjusted as desired with good reproducibility, and a porous particulate chitosan derivative having a desired cation exchange capacity O can be produced. .

[Brief explanation of the drawing]

FIG. 1 is a graph showing the relationship between sulfonating agent concentration and cation exchange capacity in Example 2 of the present invention, and FIG. 2 is a graph showing the relationship between sulfonating agent concentration and cation exchange capacity in Comparative Example 2. This is a graph showing. Patent Applicant Fujibo Co., Ltd. Agent Patent Attorney Katsu Ohno Agent Patent Attorney Reiko Ohno

Claims (1)

[Claims] 1. Low molecular weight chitosan was dissolved in an acidic aqueous solution, the solution was dropped into a basic solution, and the solidified granular porous chitosan was acetylated with acetic anhydride, crosslinked with diepoxy, and then dissolved in N,N'-dimethylformamide. 1. A method for producing a granular porous chitosan derivative having a sulfone group, characterized in that sulfonation is carried out using an N,N'-dimethylformamide-sulfur trioxide complex.