CH636097A5 - Process for preparing water-soluble hydroxyflavone ethers - Google Patents

Description

636097

2nd

PATENT CLAIMS

1. A process for the preparation of water-soluble hydroxyflavone ethers, characterized in that a hydroxyflavone is reacted with a substituted alkyl halide.

2. The method according to claim 1, characterized in that an aqueous alkali metal hydroxide solution is used as the reaction medium.

3. The method according to claim 2, characterized in that one uses a 0.5- to 5-normal aqueous alkali metal hydroxide solution.

4. The method according to claim 2 or 3, characterized in that one uses an aqueous sodium or potassium hydroxide solution.

5. The method according to any one of the preceding claims, characterized in that a halogen alcohol is used as the substituted alkyl halide.

6. The method according to claim 5, characterized in that 2-chloroethanol or 2-bromoethanol is used as the halogen alcohol.

7. The method according to any one of the preceding claims, characterized in that one uses a reaction time of 1 to 8 hours.

8. The method according to any one of the preceding claims, characterized in that one uses a reaction temperature of 30 to 90 ° C.

9. The method according to any one of the preceding claims, characterized in that 5,7,3 '- Trihydroxy-4'-methoxyflavon is used as the hydroxyflavon.

10. The method according to any one of claims 1 to 8, characterized in that the 7-rhamnoglucoside of 5,7,3'-trihydroxy-4'-methoxyflavon is used as the hydroxyflavon.

The physicochemical properties of organic compounds can often be adapted to the requirements arising from the use or handling of the compounds by forming derivatives. Although in certain cases other properties closely related to the structure, e.g. the antimicrobial activity of antibiotics, changed, such properties may be the same for certain derivatives as for the parent compound.

The solubility of a compound is very often of importance for its use in the therapeutic field, since a pharmaceutical often cannot be administered in a suitable dosage because of its low solubility in pharmaceutically acceptable solvents.

The choice of the derivatives to be produced in each individual case basically depends on the chemical structure of the compound, the properties of which are to be changed, and on the properties of the derivative. It is not always easy to achieve the desired combination of properties, since, as is well known, even minor changes in the structure very often yield derivatives whose behavior is very different in certain points from that of the starting compounds.

When a water-soluble derivative is to be prepared, it is common practice to form a suitable salt when the starting compound is an acid or base. If the compound has no acid or base character, another derivative must be prepared, the type of which can vary greatly depending on the starting compound in question.

On the other hand, it can also lead to difficulties if a compound contains several identical functional groups which are to be converted into derivatives; the respective environment of the functional groups has a major influence on their individual chemical reactivity, the influence of the neighboring atoms predominating and the influence of atoms decreasing with increasing distance from the functional group. In organic compounds, the so-called hydrogen bond is the most common type of interaction with hydroxyl groups; an atom of a strongly electronegative element, such as oxygen, shares a free electron pair to a certain extent with the hydrogen atom of the hydroxyl group. Hydrogen bonds can form within a molecule (intramolecular hydrogen bonds) or between different molecules (intermolecular hydrogen bonds, e.g. with acetic acid). The intermolecular hydrogen bonds differ from the intramolecular hydrogen bonds in that

that intermolecular hydrogen bonds are weakened by dilution to a point where there is practically no hydrogen bond at all. Intramolecular hydrogen bonds are not affected by dilution; however, their strength can also be changed by choosing a suitable solvent up to a point where the hydrogen bonds disappear.

If a molecule contains several identical functional groups whose environment is different, these functional groups behave differently. In the acetylation of dihydroquercetin, for example, a tetraacetate is formed under certain reaction conditions, in which the hydroxyl group in the 5-position is not acetylated, which is explained by the formation of a hydrogen bridge with the carbonyl oxygen in the 4-position. Other reaction conditions are required to prepare the pentaacetate; in general, however, it is contaminated with the tetraacetate. Another example is the esterification of hesperidin with nicotinyl chloride, in which, depending on the reaction conditions, an octa-, hexa-, tetra- or tri-nicotinate is obtained if pyridine or a mixture of pyridine and chloroform is used as solvent.

In the preparation of ethers of various flavonoids, it is also necessary, because of the different reactivity of the hydroxyl groups, to strictly adhere to the reaction conditions under which the desired derivatives are formed; otherwise, other compounds or more or less complicated mixtures are obtained.

The process according to the invention is particularly suitable for the production of flavone ethers which contain two free hydroxyl groups in the 5- and 3'-positions and optionally carry a further hydroxyl group in the 7-position, which is either free or bound to an organic radical. From a pharmacological point of view, these derivatives have the same vitamin P properties as the starting compounds.

The process according to the invention is characterized in that a hydroxyflavone is reacted with a substituted alkyl halide, preferably in an aqueous medium. An aqueous solution of an alkali metal hydroxide, such as sodium or potassium hydroxide, which is preferably 0.5 to 5 normal, is expediently used as the reaction medium. Halogen alcohols, in particular 2-chloroethanol or 2-bromoethanol, are preferred as substituted alkyl halides. The reaction5

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The duration is usually 1 to 8 hours. The reaction temperature is preferably 30 to 90 ° C. Suitable hydroxyflavones are 5,7,3'-trihydroxy-4'-methoxyfavon and the 7-rhamnoglucoside of 5,7,3'-trihydroxy-4'-meth-oxyflavone. The above-mentioned embodiments can be combined with one another in any manner.

example 1

100 liters of a 0.5 normal potassium hydroxide solution are placed in a glass reaction flask equipped with a reflux condenser, thermometer, heating jacket and stirrer. Then 4.5 kg of diosmin are added with constant stirring. When the diosmin has dissolved, 2.5 liters of 2-bromoethanol are added over the course of 90 minutes. The mixture is heated to reflux for no more than 4 hours and then cooled to about 40 to 50 ° C. The mixture is then distilled under reduced pressure and the residue is washed three times with pure ethanol. The washing liquids are concentrated to y} of the initial volume. The concentrated liquid thus obtained is cooled. The solids formed are separated by vacuum filtration. After recrystallization, a product with a melting point of 159 to 161 ° C. is obtained, the ultraviolet spectrum of which has absorption maxima at 252 and 340 nm.

5 Example 2

6 kg of 5,7,3'-trihydroxy-4-methoxyflavon are filled into a round-bottom flask equipped with a cooling device, heating system, thermometer and stirrer and dissolved in the smallest possible amount of a 5-normal sodium 10-hydroxide solution. A solution of 4.2 liters of 2-chloroethanol in 50 liters of water is then slowly added with constant stirring. The reaction mixture is heated so that a temperature of 70 ° C. is reached at the end of the addition. This temperature is maintained for an additional two hours. The mixture is then distilled until the residue becomes viscous. 50 liters of acetone are then added. The distillation is repeated and the residue is stirred with 100 liters of acetone for two hours. Then it is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is recrystallized. Its ultraviolet spectrum shows absorption maxima at 269 and 341 nm.

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