HU180580B - New process for preparing partially methylated beta-cyclodextrin derivatives - Google Patents

Description

A novel process for the preparation of partially methylated β-cyclodextrin derivatives

The present invention relates to a novel process for the preparation of partially methylated β-cyclodextrin derivatives.

Partially methylated derivatives of © cyclodextrin form a solid crystalline inclusion complex (Carbohydrate Research, 1979, 76, 59), following principles similar to cyclodextrins [Adv. in Catalysis, 23, 209 (1973)].

Partially methylated derivative for β-cyclodextrin means that 1-20 hydroxy groups per molecule of cyclodextrin are replaced by methyl groups. Of these products, the monomer ethyl derivative, which has an average of 7, and the dimethyl derivative, which has an average of 14 methyl groups per cyclodextrin molecule, are special. These derivatives are characterized by the average degree of substitution for the methyl groups.

Only methylation methods in organic solvents are known for the methylation of cyclodextrins, but these methods are exclusively for the preparation of pure trimethyl or dimethyl or monomethyl derivatives.

The Muskat methylation method (in liquid ammonia in the presence of metal potassium) was used for the complete methylation of β-cyclodextrin to yield crystalline hexakis (2,3,6-tri-O-methyl) -α-cyclodextrin in a single step [Berichte, 69, 2041]. 1936)]. The same procedure for © cyclodextrin yielded complete (21 methyl / cyclodextrin) methylation results only after 18 repetitions. Both «and« cyclodextrin achieved complete methylation with one form of Kuhn methylation (methyl iodide in the presence of barium oxide in dimethylformamide) (Tetrahedron, 24, 803 (1968)). Another version of Kuhn's methylation (dimethylformamide dimethylsulfoxide in a 1: 1 solvent system in the presence of barium oxide and barium hydroxide), which contains 10 crystals of hexakis (2,6-di-0-methyl) -a-cyclodextrin and hept, was also described there. , 6-di-0-methyl) - © cyclodextrin.

For the preparation of monomethyl derivatives of cyclodextrins [Bioorg. Chem., 5, 121 (1976; Star 15, 28, 226 (1976) and Starke, 26, 111 (1974)), heptakis (3-0-methyl) - © cyclodextrin and heptakis (2- O-methyl) - © cyclodextrin can be synthesized by multi-step complete syntheses, which have the common feature that the carbon atoms not methylated are protected by suitable substitution and / or the methylation reaction is carried out selectively in the presence of barium salts in an organic solvent medium. after methylation, to25 additional reaction (s) was required to liberate the protected carbon atoms.

These methods were designed to investigate the substitution of cyclodextrins as special (cyclic) oligosaccharides and the possibilities of selective partial substitution.

180,580 gals. The implementation of selective substitution is, in most cases and again, a much more difficult task than the preparation of the substituted product. All of the partially methylated and permethylated cyclodextrin derivatives known in the literature have been subjected to methylation in an organic solvent medium. For all derivatives where substitution of 3-hydroxyls was desired, barium salts were used in the organic solvent medium to ensure selectivity.

The production of purely trimetallic or various mecnomethyl derivatives is currently purely theoretical. Only heptakis (2,6-di-0-methyl) -? - cyclodextrin has been studied (Carbohydrate Research, 1979, 76, 59) for its complexing properties. Épzéshez's inclusion complex of heptakis (2,6-di-0-methyl? - ^/? - cyclodextrins addition, nen many cases, however, corresponds to one of hepbakisz (2,6-di-0-methyl) - /? - cyclodextrin suitable It is characterized by an average degree of substitution, but is also a heterogeneous product in terms of methyl group distribution.

It is an object of the present invention to eliminate, on the one hand, organic solvent media and, on the other hand, to avoid the use of their highly toxic barium salts. Not only is the use of barium salts hazardous and hazardous, but at least as great is the environmental pollution caused by the by-products of barium compounds.

According to the present invention, partially methylated / cyclodextrin derivatives having an average degree of substitution of 1 to 14 are prepared by (2 -10% by weight of J-cyclodextrin in aqueous solution at 50-100 ° C, based on the glucose units of β-cyclodextrin). - in the presence of 40 moles of alkali metal hydroxide, 9 to 30 moles of demithiumsulphate per gram of glucose units of N-cyclodextrin, and the resulting reaction mixture

(a) extracted with 2 to 5 volumes of chlorinated hydrocarbon solvent and de-solvented, or

b) desalting the hydroxyl form anion exchanger and then the hydrogen form cation exchange resin, removing the water from the resulting solution and then methylating the evaporation residue obtained according to a) or b), if desired, two to three times, and recovering the methylated product from the reaction mixture according to process a) or b) and finally purifying the methylated product obtained in the last recovery, if desired, by recrystallization.

The first methylation reaction provides products having an average degree of substitution of 1 to 3, the second having an average degree of substitution of 4 to 7 and the third having an average degree of substitution of 7 to 14. The first methylation is preferably carried out for 11 to 24 hours, the second for 24 to 36 hours and the third for 48 to 96 hours. However, these reaction times are only approximate because the reaction rate also depends on the temperature of the reaction mixture chosen. Preferably, the methylation is carried out at 50 to 70 ° C.

The alkali metal hydroxide is preferably sodium hydroxide. Examples of the chlorinated hydrocarbon used in the extraction include dichloromethane and chloroform.

Due to the fact that the β and 6 hydroxyl groups are more reactive than the other hydroxyl groups in the molecule due to their spacer structure, these hydroxyl groups are predominantly methylated during methylation. Thus, it is possible for the process according to the invention to carry out the methylation three times in succession to give a reaction product containing heptakis (2,6-di-O-methyl) -? - cyclodextrin as the main product. In this case, the residue obtained after working up the reaction mixture according to process a) or b) can be isolated by crystallization.

Further details of the invention are illustrated by the following non-limiting examples.

Example 1

Partially methylated β-cyclodextrin by single methylation

1.13 g of β-cyclodextrin is dissolved in 12 ml of distilled water at 60 ° C. While stirring at this temperature, a solution of 2.11 g of sodium hydroxide in 5 ml of water and 4.64 ml of dimethylsulphate is added dropwise over 2 hours at this temperature. After stirring for one hour at 60 ° C, a solution of 2.11 g of sodium hydroxide in 5 ml of water was added and the reaction mixture was stirred at 100 ° C for 80 minutes. The reaction mixture was cooled to room temperature and 56 g of anion exchange resin (Merck, Ionenaustauscher III) on hydroxyl form was added. The reaction mixture was stirred with the anion exchanger for 30 minutes and then filtered. 28 g of the cation exchange resin (Merck, Ionenaustauscher I) in hydrogen form are added to the filtrate until neutralization, and the filtrate is then lyophilized.

Methylated β-cyclodextrin with an average degree of substitution of 1.42 is obtained.

Example 2

Partially methylated β-cyclodextrin by triple methylation

Dissolve 1.13 g of β-tag dextrin in 60 ml of distilled water in a round-bottomed flask fitted with a magnetic stirrer. The solution was heated to 60 ° C and 14.3 ml of dimethyl sulfate and 35 ml of 20% w / w sodium hydroxide solution were added dropwise over 6 hours while stirring continuously. After stirring at this temperature overnight, 15 ml of 10% w / w sodium hydroxide solution was added and the mixture was heated to 85-90 ° C over one hour. After cooling, the reaction mixture was extracted with dichloromethane (4 x 120 mL) and the combined extracts washed with distilled water (2 x 30 mL).

It was dried over anhydrous sodium sulfate (180 580) and concentrated in vacuo.

The evaporation residue is then re-methylated as described above, except that after the addition of dimethyl sulfate, the reaction mixture is stirred at 60 ° C for 48 hours.

After methylation, the reaction mixture was worked up as described above, and the resulting evaporation residue was third methylated.

The only difference from the first methylation is that the reaction time is chosen to be 72 hours.

After the third methylation, the syrup-like residue obtained by evaporation of the extract was crystallized from chloroform-petroleum ether.

The product obtained has an average degree of substitution of 6.5.

Example 3

Heptakis (2,6-di-0-methyl) -ss-cyclodextrin

All proceed as in Example 2 with the exception that the residue obtained during the working-up of the reaction mixture for the third methylation reaction is not recrystallized from chloroform-petroleum ether but recrystallized from water. The residue was dissolved in 10 volumes of cold distilled water (10 ml) and heated to 80 ° C. Meanwhile, white, fluffy crystals are precipitated. After crystal precipitation is complete _3, the precipitated crystals are filtered through a preheated glass filter and dried in a stream of warm air. 620 mg of heptakis (2,6-di-0-methyl) -? 3-cyclodextrin are obtained in the form of a white, tiny crystalline product. 298-300 ° C [α] _D = + 150 ° (c = 1, water)

Claims (5)

Patent claims A process for the preparation of partially methylated? -Cyclodextrin derivatives having a degree of substitution of 1 to 14 with an average degree of substitution of? -Cyclodextrin in the form of an aqueous solution of 2-10% by weight of glucose units of β-cyclodextrin at 50-100 ° C. - in the presence of 40 moles of an alkali metal hydroxide, 9 to 30 moles of dimethyl sulfate per gram of glucose units of ß-cyclodextrin, and the resulting reaction mixture (a) extracted with 2 to 5 volumes of chlorinated hydrocarbon solvent, and the extract is de-solvented, or b) desalting the hydroxyl form anion exchange resin and then the hydrogen form cation exchange resin, removing the water from the resulting solution and then methylating the evaporation residue obtained according to a) or b), if desired, 2-3 times as above, and recovering the methylated product from the reaction mixture according to process a) or b) and finally purifying the methylated product obtained in the final recovery, if desired, by recrystallization. 2. A process according to claim 1, wherein the alkali metal hydroxide is sodium hydroxide. 3. The process of claim 1 or 2, wherein the reaction mixture obtained after methylation is extracted with dichloroethane. A process according to any one of the preceding claims, characterized in that the methylation is carried out at 50-70 ° C. A process for the preparation of heptakis (2,6-di-methyl) -? - cyclodextrin according to any one of the preceding claims, characterized in that the methylation is carried out three times.