CH636869A5 - Process for the preparation of flavones - Google Patents

Description

The present invention relates to a process for the production of flavones by dehydrating flavanones with elemental iodine.

Flavones are often found in nature, often colored substances, which are derived from the basic body flavone (formula I).

Of particular interest are the flavones of the general formula II which are also substituted as glycosides by hydroxy or methoxy groups,

R1 is H or a glycoside residue and R2 to R7 are each H, OH or OCH3.

Of particular pharmacological interest is diosmin, a compound of formula II,

wherein

R1

=

Rutinose,

R2

=

H,

R3

=

H,

R4

~

OH,

R5

=

OH,

R8

=

OCH3 and

R '

=

H

is.

A number of manufacturing processes for flavones, in particular for diosmin, are also known.

It is advantageous to use the partly as the starting material. 2,3-dihydro compounds also found in nature, the flavanones. The flavones can e.g. be obtained by bromination or iodination and subsequent splitting off of hydrogen iodine or bromine.

However, the yields which have hitherto been achieved with these processes are relatively low, so that the processes are out of the question for industrial production.

German patent application P 26 02 314 describes a process for the preparation of diosmin in which the yield is improved. However, only yields of around 70% are achieved here. Another disadvantage of this process is that the hydroxyl groups of the starting material hesperidin must first be carefully protected by acetyl groups which have to be removed again after the reaction.

The object was therefore to find a process which leads to a pure end product in a simple manner, if possible only in a single reaction step, in good yield.

This object has been achieved by the present invention.

It has surprisingly been found that if flavanones are dissolved in a basic solvent or solvent mixture and reacted with iodine, the flavones are formed in very good yield and purity in only one reaction step, without the need to add any hydroxyl groups which may be present protect.

The invention accordingly relates to a process for the preparation of flavones by reacting flavanones with iodine, which is characterized in that the flavanone is dissolved in a basic solvent or solvent mixture and at a temperature between room temperature and the boiling point of the solvent without isolation of an intermediate Iodine is reacted and the flavone formed is then isolated and purified in the usual way.

The procedure is in principle applicable to all flavanones. However, flavanones containing hydroxyl groups are preferably reacted, which can also be substituted by glycoside residues.

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The invention accordingly preferably relates to a process which is characterized in that from a flavanone of the general formula III,

wherein

R1 is H or a glycoside residue and R2 to R7 are each H, OH or OCH3,

a flavone of the general formula II,

wherein

R1 to R7 have the meaning given above, is produced.

In particular, however, the invention also relates to a process which is characterized in that a 7-glycoside flavanone is converted into a 7-glycoside flavone without acetylation and deacetylation of the sugar residue.

Of the hydroxyl-containing flavanones, the naturally occurring flavanones are particularly preferred as the starting material, and among these in particular hesperidin, from which diosmin can be prepared particularly advantageously by the process according to the invention.

The invention therefore relates in particular to a process which is characterized in that diosmin is prepared from hesperidin.

The advantages of the method according to the invention over those of the prior art lie in the fact that

that the flavones are obtained in very good yields and in great purity. This is surprising since the process according to the invention only works in a relatively weakly basic environment, while e.g. according to DOS 26 02 314, the splitting off of hydrogen halide from the initially formed halogenated intermediate takes place with concentrated sodium hydroxide solution. Despite these very mild conditions, the reaction is usually completed in a few hours and yields are achieved, some of which are close to 90%.

Surprisingly, it is not necessary in the process according to the invention to protect any hydroxyl groups that may be present. This represents a considerable advantage of the process according to the invention, since the complete acetylation of the starting material requires considerable expenditure, in terms of time, energy and reagents. However, e.g. in DOS 26 02 314 expressly pointed out that careful protective acetylation is important in order to arrive at a pure end product. It is all the more surprising that the end products are obtained in very good purity by the process according to the invention, even without protective acetylation, and that, above all, there is no cleavage of the glycoside residue which may be present.

Some of the flavanones that are used as raw material come in nature and can be obtained from plants using conventional methods. However, synthetic processes are also known by which a large number of flavanones can be produced. An overview of the possibilities for extracting flavanones can be found in the following monographs:

Böhm, Die Flavonoide, Verlag Editio Cantor, Aulendorf 1967 and

Geissmann, The Chemistry of Flavonoid Compounds, Per-gamon-Verlag, London 1962.

The glycoside residues which may be present can be mono-, di- and trisaccharides as well as higher saccharides. Examples include D-glucose, D-galactose, D-glucuronic acid, D-galacturonic acid, D-xylose, D-apiose, L-rhamnose, L-arabinose, rutinose and neohesperidose. Further suitable sugar residues are listed in the standard works on flavonoids .

All weakly basic solvents or solvent mixtures are suitable as solvents for the process according to the invention. Aliphatic and aromatic nitrogen-containing solvents, such as e.g. Pyridine, picolines, quinolines, lutidines and anilines and their substitution products, cyclohexylamine, diethylamine, triethylamine, triethanolamine, piperidine, morpholine, N-ethylpiperidine, N-methylmorpholine, benzylamine and N, N-dimethylbenzylamine.

Mixtures of these solvents with one another or with other solvents, such as e.g. Dimethyl sulfoxide, dimethylformamide or dimethyl acetamide. Mixtures of the solvents mentioned with water or purely aqueous solutions can also be used, it being possible for inorganic bases such as NaOH, KOH or ammonia to be used in addition to or instead of the organic bases. In general it can be said that all solvents or solvent mixtures are suitable which have a pKa value between about 5 and 11 and in which the respective flavanone is soluble. Pyridine is preferably used as the solvent.

The amount of iodine required for the reaction is in itself exactly one equivalent, and therefore this amount is generally also used. However, it is also possible to work with a lower or an excess of iodine. If iodine is used in excess, this has the advantage that the reaction is ended more quickly, but it must then be ensured that the reaction is stopped immediately after the end, in order to avoid the further reaction with the formation of undesired iodine-containing products.

You can also use the iodine in deficit. Of course, you do not get a complete conversion of the flavanon, but a mixture of flavon and flavanon. For practical purposes, it has proven advantageous to use the iodine in a small deficit, i.e. about 0.9 to 1.0 mole per mole of flavanone. Since the flavanones used as the starting material are often in contaminated form, the most advantageous range for practical purposes is 0.8 to 1.0 mol of iodine per mol of flavanone.

As already mentioned, the reaction rate during the reaction also depends on the amount of iodine used. In addition, the reaction temperature is also decisive for this. At the reaction temperatures used, which are between about room temperature and the boiling point of the solvent used, preferably at about 50 to

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about 120 ° C, reaction times are obtained which are between about 6 and about 24 hours.

After the reaction has ended, the flavones formed are isolated by methods known per se. Some of the products formed precipitate directly from the reaction medium and can be separated off by filtration or centrifugation, in some cases. however, it must first be diluted with water. In the case of hydroxyl-containing flavones, better crystallization can often be achieved if the reaction medium is adjusted to a weakly acidic pH. This can preferably be done with weak acids such as e.g. Acetic acid done. The purification or recrystallization can also be carried out by first dissolving the crude product in an aqueous / alkaline solution and then reprecipitating it by adjusting to a weakly acidic pH.

The flavones produced by the process according to the invention are notable for their exceptional purity and are practically free from organically bound iodine, so that they can be used very well for all purposes, including as pharmacologically active substances.

The broad applicability of the method is demonstrated below using a few examples.

example 1

A 60 ° C warm solution of 300 g hesperidin in 1500 ml pyridine is mixed with 122 g iodine, stirred for 12 hours at 90 ° C, cooled to 0 ° C and filtered. The filter residue is washed with water, then dissolved in dilute sodium hydroxide solution (100 ml of 32 percent by weight sodium hydroxide solution plus 450 ml of water), filtered, mixed with 400 ml of methanol and adjusted to pH 5.3 with acetic acid. The fancy

The crystals are filtered off, washed with water and dried.

A second batch can be obtained by distilling off the pyridine from the pyridine mother liquor, adding water to the distillation residue, filtering off and purifying the precipitated crystals.

A total of 264 g (89% of theory) of diosmin are thus obtained. There is no analytical evidence of iodine.

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Example 2

A solution of 5.8 g of naringin and 2.5 g of iodine in 15 ml of pyridine is stirred at 90 ° C. for 12 hours, then cooled, mixed with 40 ml of water, adjusted to pH 5.3 15 with acetic acid and filtered. After recrystallization from dimethylformamide / water (1: 1), 4.7 g (82% of theory) of rhoifolin are obtained.

Example 3

20 Analogously to Example 2, 400 mg (67% of theory) of the substance of the general formula II are obtained from 600 mg of neohesperidine,

wherein

R1 = neohesperidosis,

25 R2 = H,

Ra = H,

R4 = OH,

R6 = OH,

R6 = OCH3 and 30 R '= H,

melting point 193 ° C.

v

Claims (7)

636869 1 O R wherein R1 to R7 have the meaning given above, is produced. 1. A process for the production of flavones by dehydrogenation of flavanones with iodine, characterized in that the flavanone is dissolved in a basic solvent or solvent mixture and is reacted with iodine at a temperature between room temperature and the boiling point of the solvent without isolation of an intermediate and then formed flavon is isolated. 2. The method according to claim 1, characterized in that pyridine is used as solvent. 2nd PATENT CLAIMS 3. The method according to claim 1, characterized in that the 0.9 to 1.0 times the stoichiometric amount of iodine is used. 4. The method according to claim 1, characterized in that from a flavanone of the general formula III, wherein R1 H or a glycoside residue and R2 to R7 each denote H, OH or OCH3, a flavone of the general formula II, 5. The method according to claim 1, characterized in that a 7-glycoside flavanone is converted into a 7-glycoside flavone without acetylation and de-acetylation. 6. The method according to claim 5, characterized in that diosmin is prepared from hesperidin. 7. Flavone, produced by the process according to claim 1.