HU194917B - Process for the methylation of cyclodextrin in heterogenous phase - Google Patents

Abstract

A mixt. contg. solid alpha, beta and/or gamma cyclodextrines is methylated to obtain a methoxy content of 20-46% in the presence of an organic solvent, solid, inorganic base and a phase-transfer catalyst.

Description

The present invention relates to a process for the methylation of eicodextrins in a heterogeneous phase which results in the production of differently methylated cyclodextrins.

Methylation of some of the hydroxyl groups of cyclodextrins results in a surprisingly high water solubility, while retaining their complexing properties. In fact, the solubility enhancement is only significant for beta-cyclodextrin, since alpha and gamma cyclodextrin are already soluble in the order of magnitude more than beta-cyclodextrin. The spatial structure of beta-cyclodextrin accounts for its low solubility: beta-cyclodextrin is the stiffest structure for steric reasons. The C (2) and C '(3) hydroxyl groups of adjacent glucopyranose units form hydrogen bonds with one another. Therefore, their affinity for water is reduced. Methylation of every other secondary hydroxyl group results in an extremely high water solubility. Methylation of all hydroxyl groups again reduces the water solubility and, for technical purposes, partially methylated cyclodextrins are required.

The partial methylated derivative in the case of beta-cyclodextrin means that from 1 to 20 hydroxyl groups per molecule of cyclodextrin are replaced by methoxy groups. Of these products, the monomethyl derivative, which has an average of 7, and the dimethyl derivative, having 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.

Unlike organic methylation, hydroxyl groups of cyclodextrins are generally difficult to methylate. In each of the prior art processes, cyclodextrin had to be dissolved in a solvent to be methylated.

The first steps in the preparation of methylated beta-cyclodextrin were performed by Irvine et al. (Irvine, J.C., Pringsheim, H., Mac Donald, J.: J. Chem. Soc., 125, 942 (1942)). Freudenberg (K. Freudenberg, Meyer-Delius, M. Bér. 71, 1596, (1938)) was the first to report correct physical properties by the Muskat methylation process (Muskat, 1: J. Am. Chem. Soc., 56). , 693, 2449, (1934)). This methylation was performed in liquid ammonia in the presence of metal sodium with methyl iodide. The same procedure yielded a total of 21 methyl / cyclodextrin methylation results only 18 times for beta-cyclodextrin.

Later, Casu et al. (Casu, B., Reggiani, M., Gallo, G.G., Viegevani, A .: Tetrahedron, 24, 803, (1968)) Kuhn's method (Kuhn, R., Trischmann, H., Löw, I. Angew. Chem., 67, 32 (1955) and Kuhn, R., Baen, H.H., Seeliger, A., Ann., 611, 236 (1958)) were used to methylate alpha and beta-cyclodextrin. Methyl iodide was fully methylated in dimethylformamide medium with methyl iodide, or another variant of Kuhn methylation, methylated with dimethyl sulfate in dimethylformamide dimethyl sulfoxide 1: 1 in the presence of barium oxide and barium hydroxide in hexac -O-methyl) -alpha-cyclodextrin and heptakis (2,6-di-0-methyl) -beta-cyclodextrin were prepared.

Lipták et al. (Lipták, A., Fügedi, P., Szurmai, J., Imre, P., Nánási, P., Szejtli, J., I. Int Symp.on Cyclodextrins, Budapest, 275 (1981); and Szejtli, J., Lipták, A., Iodal,

I., Fügedi, P., Nánási, P., Neszményi, A .: Starke, 32, 165 '(1980), described the preparation of permethylated alpha, beta and gamma cyclodextrins by dissolving anhydrous cyclodextrin in dimethylformamide and methyl iodide. Similarly, Boger et al. (Boger, J., Corcoran, R. J., Lehn, J.M. Helv. Chim.Acta, 61, 2190 (1978)) carried out the selective methylation of the primary hydroxyls of alpha and beta cyclodextrin.

Casu et al., In their above-mentioned work, disclose that anhydrous dimethyl sulfoxide in a 1: 1 solvent system in the presence of a large amount of barium oxide and barium hydroxide can be methylated with dimethyl sulfate to produce heptakis (2,6-di-0-methyl) -beta-cyclodextrin. Because this compound is of pharmaceutical technology importance (Szejtli, J.: I. Inclusion Phenomena, 1, 153 (1984)), attempts have been made to make it easier, less expensive. No. 180,580. According to a Hungarian patent, methylation in aqueous medium in the presence of sodium hydroxide is carried out with dimethyl sulfate at 50-100 ° C, and after isolation the product has to be methylated several times, followed by chromatography on the methylation process, and DIMEB isolated after the third methylation. The literature on the preparation of methylated cyclodextrins is summarized in two books, J. Szejtli, Cyclodextrins and their Inclusion Complexes, Akadémiai Kiadó, Budapest, 1982 and J. Szejtli, (Ed.); Proceedings of the I. International Symposium on Cyclodextrins, Academic Publisher, Budapest, 1982.

Thus far, only methylation of cyclodextrins dissolved in water, organic solvent, or liquid ammonia has been described. Surprisingly, it has been found that cyclodextrins can be methylated in a heterogeneous phase, i.e., an organic solvent in which the cyclodextrin does not dissolve. This has the great advantage of using organic solvents which are inexpensive, easy to distill, and thus well regenerated, since cyclodextrin is insoluble and does not cause high viscosity, so that methylation can be performed at a much more favorable solvent: cyclodextrin ratio. Undoubtedly, the methylation carried out in this way is not selective for any of the products, but results in the partial methylation of cyclodextrins to varying degrees, and can be prepared, if desired, by trimethyl-2194917

-cyclodextrint too. The present invention is based on the use of a phase transfer catalyst for the methylation and reaction of both cyclodextrin and base in solid state. Already methylated cyclodextrins are dissolved in the reaction mixture.

Because cyclodextrins contain a large number of hydroxyl groups with different reactivities, the production of homogeneous methylated cyclodextrins is very problematic. In some cases - e.g. pharmaceuticals - it is essential that the substance be homogeneous and contain only one type of compound. However, in the case of beta _z -cyclodextrin, the methylation of the hydroxyl group 21, in the case of non-permethylated cyclodextrin, can be a mixture of extremely large number of position isomers. Research into the properties of methylated cyclodextrins has revealed their wide range of applications based on the fact that methylated cyclodextrins act as a new type of detergent against hydrophobic substances. Thus, for many technical purposes, it is not necessary to have a perfectly homogeneous product, but a mixture of homologues and isomers that are methylated to varying degrees, with only very high technical difficulty and very expensive separation. These materials are also heterogeneous mixtures of homologous and isomeric materials, e.g. detergents used in practice. They can be characterized by average degrees of methylation, but in practice they are most important in their ability to hydrophilize hydrophobic compounds. The average degree of methylation refers to the average number of hydroxyl groups in the cyclodextrin molecules.

Thus, for such technical purposes, mixtures of methylated cyclodextrin of heterogeneous but defined composition, yet relatively inexpensive, are required. The use of known processes for the production of such products practically precludes economic and technical problems. Some of these problems are expensive solvents that are difficult to regenerate, relatively low concentrations due to high viscosity, the need for multiple re-methylation in water as solvent, the price of methyl iodide for liquid ammonia, etc.

The product of the present invention can be conveniently used for biological conversions, for example when converting hydrocortisone to prednisolone. The following examples illustrate the details of our procedure.

EXAMPLES

Example 1

Into a four-necked round bottom flask equipped with a stirrer, a thermometer and a dispensing aperture were charged 5 g (4.4 mmol) of β-cyclodextrin, 200 cm ^{3 of} dry tetrahydrofuran, 12.75 g (227.3 mmol) of powdered potassium hydroxide and 1 g of tricapryl.

methyl ammonium chloride (Aliquat 336) phase transfer catalyst. The reaction mixture was cooled with ice water and added dropwise at 0-5 ° C

5.85 cm ³ (61.6 mmol) of dimethyl sulfate and stirred for 7 hours. The next day while cooling, 2 cm ³ (21 mmol) of dimethyl sulfate was added dropwise to the stirred reaction mixture and stirred for 6 hours, again overnight: 2 cm ³ (21 mmol) of dimethyl sulfate was added dropwise to the cooled reaction mixture Stir for 6 hours.

The reaction mixture is filtered through a pleated filter, 3 cm ^{3 of} concentrated ammonium hydroxide solution are added to the filtrate and the mixture is stirred for 1-2 hours at room temperature and then evaporated to dryness in vacuo. The residual syrup was extracted with ³ x 15 cm ^{3 of} lukewarm water, and the combined aqueous extracts were filtered on a pre-moistened pleated filter paper. The aqueous solution was evaporated in vacuo and the residue is dissolved in 40 cm ³ of chloroform, filtered through fluted filter paper, evaporated in vacuo to dryness. A white, foamy, amorphous product is formed. Yield: 3.92 g.

Measured by the Zeiss method, the product has a methoxy content of 29.1% and an average methylation degree of 12.4.

Water solubility at 22 ° C: 23 g (100 ml) solution opalescent at 70 ° C), freely soluble in chloroform.

Example 2

The reaction was carried out and worked up as described in Example 1, except that 200 cm ^{3 of} benzene were used as solvent.

Yield: 1.5 g. Methoxy content: 29.5%, average degree of methylation 12.6.

The solubility is the same as that of Example 1.

Example 3

The reaction was carried out and worked up as described in Example 1, except that 200 cm ^{3 of} solvent were used.

1,2-dichloroethane is used.

Yield: 3.03 g. The methoxide content is 30.6%, the average degree of methylation is 13.1.

Water Solubility: 26 g (100 mL) of solution opalescent at 65 ° C), freely soluble in chloroform.

Example 4

The apparatus described in Example 1 was charged with 2 g (1.76 mmol) of β-cyclodextrin, 80 cm ^{3 of} dry tetrahydrofuran, 5.1 g (90.9 mmol) of powdered potassium hydroxide and 0.4 g of TBAB (tetrabutylammonium). bromide) phase transfer catalyst. To the reaction mixture was added dropwise 2.35 cm ³ (24.6 mmol) of dimethyl sulfate at room temperature with stirring and stirred for 7 hours. After standing overnight, the reaction mixture is filtered on paper and concentrated in vacuo. The residue was dissolved in 30 cm @ ^{4 of} chloroform and washed with 5 cm @ ^{3 of} water. The chloroform phase was sodium sulfate

The mixture was dried over <RTIgt; -3194917, </RTI> filtered and concentrated in vacuo.

Yield: 0.25 g. The methoxide content is 29.1%, the average methylation degree is 12.4.

Water solubility: 30 g (100 ml) of solution opalescent at 65-70 ° C), freely soluble in chloroform.

Example 5

The apparatus described in Example 1 was charged with 5 g (4.4 mmol) of β-cyclodextrin, 200 cm ^{3 of} dry tetrahydrofuran, 12.75 g (227.3 mmol) of powdered potassium hydroxide and 1 g of Aliquat 336 phase transfer catalyst. To the reaction mixture was added dropwise 8.8 cm ³ (92.4 mmol) of dimethyl sulfate with stirring at room temperature and the mixture was stirred at 50 ° C for 5 hours. After standing overnight, dimethyl sulfate (1.8 cm ³ , 18.5 mmol) was added to the reaction mixture at room temperature and stirred at 50 ° C for 6 hours. The cooled reaction mixture was worked up as described in Example 1.

Yield: 3.0 g. Methoxide content 30.9 g%, average degree of methylation 13.2.

Water solubility: 34 g (100 ml) solution opalescent at 65-70 ° C), freely soluble in chloroform.

Example 6

The reaction was carried out and worked up as described in Example 1, except that 1 g of barium oxide was added as a base in addition to potassium hydroxide.

Yield: 1.4 g. The methoxide content was 30.7%, the average degree of methylation was 13.1.

Water solubility: 45 g (100 ml) of solution are opalescent at 60 ° C, white precipitate precipitates, freely soluble in chloroform.

Example 7

To the apparatus equipped with a reflux condenser was added 0.5 g (0.44 mmol) of beta-cyclodextrin, 20 cm ^{3 of} tetrahydrofuran, 0.6 g (15 mmol) of powdered solid sodium hydroxide, 0.1 g of Aliquat 336 catalyst, and at room temperature. 0.7 cm ³ (11 mmol) of methyl iodide was added dropwise with stirring. The reaction mixture was heated at reflux for 5 hours with stirring. Work up as described in Example 1.

Yield: 0.15 g. The methoxide content is 29.2%, the average degree of methylation is 12.5.

Water solubility: 28 g (100 ml) of solution is opalescent at 75 ° C.

Example 8 Methylation of α-cyclodextrin

Into a 250 cm ³ flask equipped with a stirrer, a thermometer, a condenser and a dropping funnel were charged 5 g (5.14 mmol) of α-cyclodextrin, 1.0 g of Aliquat 336 catalyst,

12.75 g (227.25 mmol) of powdered potassium hydroxide and 82 cm ^{3 of} dry THF. To the stirred mixture was added dropwise a solution of 17.6 cm ³ (184.8 mmol) of dimethyl sulfate in 18 cm ^{3 of} dry THF at room temperature over 2 hours. After the addition was complete, the reaction mixture was heated to 50 ° C and stirred at this temperature for 4 hours. Let it stand overnight. The next day the reaction was filtered on paper and the filtrate was added in 3 cm ³ of 25% NH _3, was added, which was allowed to stand for 1-2 hours. The whole is then evaporated to dryness in vacuo, the residue is taken up in 50 cm ³ of water at 30 ° C, filtered through filter paper, taking care not to allow the Aliquat catalyst to pass through. The filtrate was evaporated to dryness in vacuo. The residue was taken up in chloroform and filtered for insoluble material. The chloroform filtrate was evaporated to dryness in vacuo. A white solid is formed.

Yield: 5.78 g. Methoxy content: 26.70% (Zeissel method)

EXAMPLE 9 Methylation of γ-cyclodextn'n: By the procedures and procedures described in Example 8.

Yield: 4.3 g. Methoxy content: 28.50% (Zeissel method)

One of the most characteristic functional properties of methylated cyclodextrins is that they significantly increase the water solubility of hydrophobic substances. This is also the case for unsubstituted cyclodextrins, but the solubility enhancement is lower.

Example 10

Flammability tests (hydrocortisone) were carried out with substrate in distilled water at room temperature with stirring for 18 hours.

mg (~ 0.037 mmol) of the methylated β-cyclodextrin product of Examples 1, 2, 3, 6 were stirred with hydrocortisone (67 mg, 0.185 mmol) at 25 ° C in 1 mL of distilled water for 18 hours. The mixture was filtered and the hydrocortisone content of the crude solution was determined by UV photometry at kmax = 248 ± 2 nm. The results of the solubility tests are shown in Table 1. are summarized in Table.

, Spreadsheet

Solubility enhancement effect of methylated g-cyclodextrin on hydrocortisone substrate, / t = 25 ° C / in distilled water.

Methylated Hydrocortisone Solubility Product Concentration in Water Yug / ml 470-485 *

4.000 ~ 8 x of Example 6

3.050 ~ 6 x of Example 3

-4194917

Table 1 (continued)

methylated hydrocortisone Solubility product concentration enhancement µg / ml in water 5 Example 1 of 3500 7x Example 2 10 of 3800 8x

pure heptakis (2,

6-di-0-methyl) j3-cyclodextrin

8,000 x

* basic solubility of hydrocortisone in water at 25 ° C.

Unmethylated cyclodextrins at the above concentrations resulted in the following solubility enhancement:

CD 980-1050 µg / ml ~ 2 x β CD (1.8% solution) 2200 pg / ml ~ 4.5 x γ CD 4000 pg / ml ~ 8 x

Example 11

Chromatographic characterization

Simple, rapid analytical characterization of the methylation products is conveniently carried out by layer chromatography. Chromatograph on silica gel G in the following solvent mixture:

benzene-methanol 8: 2 benzene-methanol 7: 3

Layer chromatography of the products prepared by the methods described in the Examples shows that heptakis-2,6-di-0-methyl-beta-cyclodextrin is the major product and 3-6-under- and over-methylated β-cyclodextrin can also be detected.

The Rf values of the components in benzene-methanol 8: 2 are as follows:

(2,6-di-0-methyl) -β-cyclodextrin 0.48-0.52 over-methylated product: 0.55 under-methylated product: 0.40

0.36

0.30

0.22

0.18

0.10

Rf values in benzene-methanol 7: 3:

heptakis (-2,6-di-0-methyl) β-cyclodextrin: 0.58-0.62 over-methylated product: 0.66 under-methylated product: 0.50

0.46

0.40

0.35

0.33

0.20

Examination of the layer chromatography showed that 60 to 70% of the partially methylated cyclodextrins obtained as the main components of the examples were formed as heptakis di-O-methylcyclodextrins, which were present as a mixture of position isomers and further methylated to yield the permethylated derivative.

Example 12

Stirrer, thermometer, was charged with 5 g of conversion was (24% β-CD, 12% alpha CD, 15 2% y-CD, 62% water, linear dextrins and other accompanying materials) in 250 cm ³ of abs four-necked flask equipped with metering orifice. tetrahydrofuran and 1 g of tricaprylmethylammonium chloride phase transfer catalyst. The reaction mixture was cooled with ice water and 5.9 cm ^{3 of} dimethyl sulfate was added dropwise at 0-3 ° C with constant stirring. The reaction mixture was then stirred for 12 hours at 22 ° C, while the methylation was monitored by TLC. The reaction mixture was worked up as described in Example 1. Yield: 4.0 g of yellowish honey-like syrup. The product has an unlimited water solubility at 22 ° C and does not opalesce when heated. The solubility of the substance in a 5% solution on hydrocortisone test30 is 1650 pg / ml.

Claims (6)

PATENT CLAIMS 35 1) A process for the preparation of a mixture of alpha-beta and / or gamma-cyclodextrins having varying degrees of substitution on average of 10-24 degrees of substitution by methylation, characterized in that it is a solid alpha, beta and / or Methylation of 40 gamma-cyclodextrin was performed in the presence of an organic solvent, a solid inorganic base and a phase transfer catalyst. 2. The process according to claim 1, wherein the alpha-, beta- and / or gamma-cyclodextrin is methylated by suspension in an organic solvent. 3.) In steps 1-2. Process according to Claim 1, characterized in that the organic solvent used is ₅ θ aromatic hydrocarbon, ether, halogenated hydrocarbon, preferably tetrahydrofuran. 4. The process of claim 1 wherein the methylating agent is dimethyl sulfate or methyl halide. 5. A process according to claim 1, wherein the inorganic base is an alkali metal and / or alkaline earth metal hydroxide, 60 oxides, carbonates, preferably potassium hydroxide. 6. A process according to claim 1, wherein the phase transfer catalyst is tricaprylmethylammonium chloride.