HU202253B - Process for producing water soluble cyclodextrin polymeres of low salt content - Google Patents

Abstract

Prepn. of condensn. prods. of low salt content between substitd. cyclodextrines and epoxy cpds. in the presence of insol. basic polyelectrolytes. The latter is added to the otherwise customery aq. basic reaction mix at 10-600 wt.% (based on cyclodextrine). Opt., the cyclodextrine soln. is also passed consecutively through ion exchange columns in the H+ and OH- forms respectively.

Description

The present invention relates to a process for the preparation of low salt condensation derivatives of cyclodextrins and epoxy compounds optionally containing substituent (s).

Cyclodextrins are widely used in the so-called. formation of inclusion complexes that allow the use of many organic compounds in advantageous (more soluble or more stable) forms. Cyclodextrins are non-reducing cyclic oligosaccharides consisting of 6, 7 or 8 α-D-glucopyranosyl units. The α-D-glucopyranosyl units are attached at the 1,4-position. Α-cyclodextrin 6, β-cyclodextrin 7, and γ-cyclodextrin 8 are composed of α-D-glucopyranosyl units. The basic units can be converted to a wide variety of compounds by attaching different substituents.

For some applications, polymers obtained by linking some cyclodextrin base units are preferred. They may be prepared by converting a cyclodextrin or a mixture of cyclodextrins into a condensation product by reaction with a suitable polyfunctional compound, usually epoxy compounds (e.g. epichlorohydrin). In these reactions, it participates with hydroxyl groups of cyclodextrin, while e.g. hydrochloric acid is liberated. Such a procedure is described, for example, in British Patent No. 1,244,990 and U.S. Patent No. 4,274,985.

A common feature of the described processes is that large amounts of alkali metal hydroxides, mostly sodium hydroxides, are used for the condensation reaction with epichlorohydrin. This forms sodium chloride with the resulting hydrochloric acid, whereby the soluble condensation products are characterized by a relatively high salt content. This salt content can only be time consuming and costly, e.g. can be removed by dialysis. This operation places a significant burden on manufacturing technology and is a barrier to the spread of large-scale processes.

It is an object of the present invention to provide a process which avoids the formation of large amounts of salt during the condensation reaction and eliminates the need for desalting by dialysis, or the amount of residual salt is so small that, e.g. removable by ion exchange.

The present invention is based on the discovery that the above object can be achieved by replacing most of the required alkali metal hydroxide with a basic polyelectrolyte, so that the cyclodextrins and the epoxy compound are reacted at high speed without significant amounts of salt being formed in the reaction mixture. In this way, the

Instead of solutions containing 15 to 17% by weight of salt, a solution with a salt concentration of less than 1% by weight is formed.

Accordingly, the present invention relates to a process for the preparation of low-salt condensation derivatives of cyclodextrins (or cyclodextrin derivatives) and epoxy compounds, which comprises concentrating the cyclodextrin (s) and the epoxy compound in the presence of an insoluble basic polyelectrolyte. is added to a conventional reaction mixture, preferably aqueous to alkaline, in an amount of 100 to 600% by weight of cyclodextrin, and optionally the resulting cyclodextrin solution is desalted with a cation exchange resin in its H-form and then an anion exchange resin in OH form. over.

Studies on the selection of suitable polyelectrolyte have shown that styrene / divinylbenzene copolymers containing quaternary ammonium groups can be used very effectively for this purpose. Otherwise, these materials are widely used in ion exchange technology.

Commercially available products swell in water but are practically insoluble. They contain highly basic groups covalently bonded to the matrix at a concentration of 3 to 3.5 milliequivalents / g. Prior to use, the polyelectrolyte is converted to the OH form with a strong mineral alkali and added to the reaction mixture containing otherwise conventional materials. The minimum amount of polyelectrolyte required is equivalent to the hydrochloric acid formed in the reaction.

Given that the polyelectrolyte used is suitable for use in packed columns, the process of the present invention may be readily continuous (in the case of a medium miscible crosslinker). The solution containing the reaction components is then passed through a heated column containing the resin previously converted to the OH form.

The main advantages of the process according to the invention are:

1. The water-soluble cyclodextrin polymer solution formed in the reaction does not contain or contains only a small amount of salt, so that the expensive and laborious purification steps (dialysis) used up to now may be omitted or replaced by other more efficient methods (eg ion exchange desalination).

2. Reduced alkali content and low salt concentration reduce the corrosion problems in the apparatus.

3. In some cases, the procedure can be easily made continuous.

In order to carry out the process of the invention, the following embodiments are provided.

Example 1 liter stirrer, condenser, dropping funnel and a thermometer placed in 108 cm ³ of distilled water and 12 g of NaOH in dissolved. 28.4 g of monochloroacetic acid (Reanal), followed by 170 g of β-cyclodextrin (Chinoin) are added to the alkali with stirring and stirred at room temperature for 40 minutes. A further 12 g of NaOH are dissolved in 36 cm ^{3 of} distilled water and added dropwise to the flask at a rate of 1 cm ³ / min. The flask contents were heated to 60 ° C and maintained at this temperature for 60 minutes. In a separate vessel, 900 cm ^{3 of} Varion AD basic anion exchange resin (Nitrochemistry) was heated with water (250 cm ³ ) to 60 ° C and transferred to the flask. At constant temperature, 138.7 g of epichlorohydrin (Schering) was added over 1.5 hours and then stirred at 60 ° C for an additional 10 hours. The reaction was quenched and the resin was filtered off.

The filtrate is slightly alkaline with a dry solids content of 251 g and a NaCl content of 1% by weight.

The filtrate was further purified by passing through Varion KS-H acid cation exchange columns and Varion AD-OH basic anion exchange columns. The final product thus obtained is essentially salt-free.

HU 202253 Β

Example 2

The Al procedure is the same as in Example 1 except that 850 cm ^{3 of} Varion AT highly basic anion exchange resin is added to the system. The properties of the final product are within the value given in Example 1.

Example 3

The procedure is the same as in Example 1 except that monochloroacetic acid is not added at all and the second portion of NaOH is only 6 g. The resulting soluble polymer is in this case neutral.

Example 4

The procedure is the same as in Example 1 except that 118 ml (138 g) of dimethylammonium chloride are added to the system instead of monochloroacetic acid.

Example 5

The procedure differs from Example 1 by adding alpha cyclodextrin instead of beta cyclodextrin.

Example 6

The procedure differs from Example 1 in that gamma cyclodextrin is added to the system instead of beta cyclodextrin.

Example 7 108 cm ^{3 of} distilled water were added to a flask equipped with a dm ³ stirrer, a condenser, a dropping funnel and a snow meter and dissolved in 12 g of NaOH. The liquor with stirring, 28.4 g of monochloroacetic acid and 170 g of β-cyclodextrin were added and stirred at room temperature for 40 minutes, further 36 cm ³ of distilled water, 12 g of NaOH are dissolved and a solution rate of 1 cm ³ / min to the flask. After mixing with 200 cm ^{3 of} water, 101.2 cm ^{3 of} glycerol triglycidyl ether was added to the flask with stirring and the temperature was raised to 60 ° C. A filter-bottomed column with a 50 mm diameter heated jacket is charged with 900 cm ^{3 of an} OH-form Varion AD basic anion exchange resin and teppered at 60 ° C with water flowing through the jacket. The mixture prepared above was passed through the column at a rate of 20 cm ³ / hr. The filtrate is slightly alkaline and contains 0.5% NaCl.

Example 8

The procedure of Example 7, except that it passes through the column filled with an ion exchanger, follows the procedure of Example 2.

Example 9

The procedure of Example 7, except that it passes through the column filled with an ion exchanger, as in Example 3.

Example 10

The procedure of Example 7, except that it passes through the column filled with an ion exchanger, follows the procedure of Example 4.

Example 11

The procedure of Example 7, except that it passes through the column filled with an ion exchanger, as in Example 5.

Example 12

The procedure of Example 7, except that it passes through the column filled with an ion exchanger as in Example 6.

Example 13

138 g of β-cyclodextrin are dissolved in a mixture of 300 cm ^{3 of} water and 68 g of NaOH. 22.5 g of dimethylammonium chloride are added. Stir for 1 hour at 60 ° C. The resulting mixture was an alkaline solution of dimethylamino-β-cyclodextrin, to which 150 cm ^{3 of} Varion AD basic anion exchange resin were added and 94.7 cm ^{3 of} epichlorohydrin was added dropwise. After stirring at 60 ° C for 10 hours, standing overnight, it was filtered and desalted as in Example 1.

Example 14 2,6-Di-O-methyl-3-cyclodextrin (g) is mixed with 60 cm ^{3 of} water and 100 cm ^{3 of} Varion AD basic anion exchange resin and 14.5 cm ^{3 of} epichlorohydrin are added. Stir for 15 hours at 60 ° C. Then it is

Filter as in Example 1 and desalt.

EXAMPLE 75 In a dm ³ flask equipped with a stirrer, a condenser, a dropping funnel and a thermometer, 108 cm ^{3 of} distilled water were added and 12 g of NaOH were dissolved. 28.4 g of monochloroacetic acid, followed by 170 g of β-cyclodextrin are added with stirring and the mixture is stirred at room temperature for 40 minutes. A further 12 g of NaOH are dissolved in 36 cm ^{3 of} distilled water and added dropwise to the flask at a rate of 1 cm ³ / min. The contents of the flask were heated to 60 ° C and maintained at this temperature for 60 minutes (solution I). A Varion AD resin loaded with 900 cm ^{3 of} hydroxyl form is placed in a 30 mm diameter double wall glass ion exchange column and heated to 60 ° C with water flowing through the jacket. The column (I) is used to circulate solution (I) through a column pump at a linear rate of 0.1 m / min, so that the passage is always returned to the feed tank. 138.7 g of epichlorohydrin was added dropwise to the same container over 1.5 hours. After completion of the dropwise addition, the solution was passed through the column for an additional 30 minutes. The material thus obtained (solution Π) was passed through a series of Varion KS-H and Varion AD-OH ion exchange columns. The drained liquid (solution III) has a substantially salt-free dry matter content of 230 g.

Example 16

The procedure was the same as in Example 15 except that 194 g of γ-cyclodextrin was used as starting material instead of β-cyclodextrin.

Example 77

The procedure was the same as in Example 15 except that 146 g of α-cyclodextrin was used as starting material instead of β-cyclodextrin.

Claims (7)

1. Process for water-soluble, optionally substituted cyclodextrin polymers having up to 1% by weight salt HU 202253 Β by concentration of optionally partially substituted α-, β- or γ-cyclodextrin and epoxy, characterized in that it is optionally partially substituted α-, β- or γ-cyclodextrin optionally formed in situ by substitution of 5 cyclodextrin and the condensation of the epoxy compound is conveniently carried out in an aqueous-alkaline medium in an amount of from 100 to 600% by weight of cyclodextrin in the presence of a water-insoluble basic polyelectrolyte at a temperature of about 60 to 60 ° C. in this case, it is further passed through a desalination unit consisting of a cation exchange resin in the H-band followed by an anion exchange resin in the OH form. Process according to claim 1, characterized in that the starting material is an α-, β- or γ-cyclodextrin partially substituted with a cationic group, preferably a C2-C5 carboxyalkyl, most preferably a carboxymethyl group. 3. The process according to claim 1, wherein the starting material is β-cyclodextrin, which is partially substituted with an anionic group, preferably di (C1-C4) alkylamino, most preferably dimethylamino. Process according to claim 1, characterized in that the starting material is β-cyclodextrin partially substituted by a neutral group, preferably a C 1 -C 4 alkyl group, most preferably a methyl group. 5. The process according to any one of claims 1 to 3, wherein the basic polyelectrolyte is a quaternary ammonium crosslinked ion exchange resin, which is converted to its hydroxide form before use. 6. The process according to claim 5, wherein the crosslinked ion exchange resin is a styrene / divinylbenzene copolymer. 7. Process according to any one of claims 1 to 3, characterized in that the substances involved in the concentration reaction are dissolved in a suitable solvent, preferably aqueous and / or alkaline, and passed through a packed column containing the polyelectrolyte.