CH644132A5 - Process for the preparation of the flavone glycosides diosmin, neodiosmin and rhoifolin - Google Patents

Description

644 132

2nd

PATENT CLAIMS

1. A process for the preparation of the flavone glycosides diosmin, neodiosmin or rhoifolin by oxidation of the flavanone glycosides, hesperidin, neohesperidine or naringin, characterized in that one of the flavanone glycosides is treated with iodine in aqueous alkaline solution, the intermediate product of a treatment in strongly alkaline aqueous solution subject and then the flavone glycoside precipitates and separates by acidification.

2. The method according to claim 1, characterized in that one uses 1 to 1.5 moles of iodine per mole of flavanone glycoside.

3. The method according to claim 1, characterized in that the iodine is dissolved in an organic, preferably nitrogen-containing solvent or used as a Kb complex in aqueous solution.

4. The method according to claim 1, characterized in that the reaction of the flavanone glycoside with iodine takes place at a temperature between room temperature and the boiling point of the reaction mixture, in particular between 20 and 110 ° C.

There are several options described in the literature for converting flavanone glycosides into the corresponding flavone glycosides. These changes are known to occur through dehydrogenation at carbon atoms 2 and 3 of the aglycon. For example, hesperidin is replaced by elemental bromine (Reports of the German Chemical Society, volume 32, page 326 (1899); volume 33, page 362 (1900); volume 37, page 2634 (1904); volume 76, page 452 (1943) ) brominated with N-bromosuccinimide, pyridine bromide perbromide (Journal of Organic Chemistry, Volume 16, page 930 (1951)) or tri-phenylphosphine-2-carboxyethyl bromide perbromide (Spanish Patent No. 459 076) and to a diosmin by subsequent alkaline hydrogen bromide elimination dehydrated. The same can be achieved directly with SeCh (Journal of Indian Chemistry Society, Volume 31, page 565 (1954)) or with 2,3-dichloro-5,6-dicyano-p-benzoquinone. Acidic iodine has also been used oxidatively (Proceedings of the Indian Academy of Science, volume 30, page 151 (1949) and Journal of Organic Chemistry, volume 30, page 4346 (1965)). However, all of these methods have a number of disadvantages. The operations are cumbersome and lengthy, especially since it was assumed that the OH groups of the sugars, especially those of rutinose and neo-hesperidosis, had to be protected by acetylation. In addition, the oxidations, dehydrations and brominations rely on organic solvents, which are usually expensive, dangerous and not very environmentally friendly. Surprisingly, all of these disadvantages can be avoided by using the method according to the invention below. The invention relates to the method defined in the patent claim. The process is carried out in an alkaline, aqueous phase. Elemental iodine serves as the oxidizing agent. It is expediently used in a slight excess, based on equivalent ratios. The iodine can either be in its water-soluble form as a complex with potassium iodide as KJ3 or dissolved in small amounts of nitrogenous solvents, e.g. Pyridine, diethylamine or diethanolamine, or even more simply used in methanol. The oxidation takes place via an intermediate product containing iodine, and the iodine can be removed with alkalis or potassium tert-butylate. In this way, as shown in the following examples, hesperidin is converted into diosmin, neo-hesperidin in neo-diosmin and naringin in rhoifolin (api-genin-7-neohesperidoside) without complications. The following. percentages of concentration are by weight.

example 1

6.1 g of hesperidin are dissolved in a mixture of 20 ml of distilled water and 7 ml of 15% sodium hydroxide solution, and the mixture is stirred at room temperature for 15 minutes. A solution of 2.5 g of iodine in 3 ml of pyridine is then added and the solution is boiled for 3 hours, during which a precipitate forms. The pH of the solution, which was originally 12, is reduced to 10 during the precipitation. The reaction mixture is allowed to cool, filtered and the light yellow crystals are washed with warm water and methanol. After drying at 60 ° C in vacuum, 4 g of diosmin (about 66%) with a melting point of 270 ° C are obtained. For cleaning, the product is dissolved in a mixture of 50 ml of 96% ethanol and 20 ml of 15% NaOH and heated to 70 ° C. for 30 minutes. It is filtered while still warm and the filtrate is brought to a pH of 5 to 6 with acetic acid. Diosmin precipitates in crystalline form. It is suctioned off and washed with warm water and methanol. After drying in vacuo at 60 ° C, a product is obtained which melts at 280 ° C. Yield 52%.

Example 2

6.1 g of hesperidin are dissolved in a mixture of 20 ml of water and 10 ml of 15% sodium hydroxide solution and the mixture is stirred at room temperature for 15 minutes. Then 2.5 g of iodine and 3.6 g of potassium iodide in 10 ml of water are added. The reaction mixture is boiled for 3 hours, a yellowish precipitate separating out. It is suctioned off and the crystals are washed with warm water and methanol. After drying in vacuo at 60 ° C, 2.9 g (48%) of a product are obtained, which melts at 250 ° C. This product is dissolved in a mixture of 50 ml of 96% ethanol and 20 ml of 15% NaOH and heated to 70 ° C. for 30 minutes. Filter while still warm and bring the filtrate to a pH between 5 and 6 with acetic acid. Diosmin precipitates in crystalline form. You vacuum and wash with warm water and methanol. Dried in vacuo at 60 ° C., 2.4 g of diosmin are obtained (42%), which melts at 270 ° C.

Example 3

6.1 g of neohesperidine are dissolved in a mixture of 20 ml of water and 7 ml of 15% strength NaOH and the mixture is stirred for 15 minutes. Then 2.5 g of iodine in 2 ml of dimethylformamide are added and the solution is boiled for 3 hours. When cooling down, a yellowish precipitate slowly forms. It is suctioned off and the precipitate is washed with warm water and methanol and dried in vacuo at 60 ° C. 2.6 g (about 43%) of a product with a melting point of 203 to 208 ° C. are obtained. The product is dissolved in a mixture of 50 ml of 96% ethanol and 25 ml of 15% sodium hydroxide solution and heated to 70 ° C. for 30 minutes. The mixture is then filtered and the filtrate is acidified to a pH of 5 to 6 with acetic acid. A yellowish, granular, crystalline precipitate of neodiosmin is formed, which is separated off, washed with warm water and methanol and dried in vacuo at 60.degree. The yield is 2.3 g (48%) of the melting point 190 ° C.

Example 4

6.1 g of naringin are dissolved in a mixture of 15 ml of water and 7 ml of 15% sodium hydroxide solution and the mixture is stirred at room temperature for 15 minutes. Then add 2.5 g iodine in 3 ml s

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Pyridine and boil the solution for 3 hours. The pH of the solution is 11. After cooling, water is added to a volume of 500 ml and acidified to a pH of 5 to 6 with acetic acid, whereby a yellow product of granular nature precipitates. This product is separated off, washed with distilled water, dried in vacuo at 40 ° C. and 4.5 g of a product (about 75%) with a melting point of about 180 ° C. are obtained. This product is dissolved in a mixture of 50 ml

Ethanol 96% and 20 ml sodium hydroxide solution 15%, and heated to 70 ° C for 30 minutes. After filtration, the filtrate is acidified to a pH of 5 to 6 with acetic acid, a yellowish crystalline product precipitating, which is separated off and washed with cold water. After drying in vacuo at 60 ° C, 4.2 g of apigenin-7-neohesperidoside (Rhoifolin) are obtained (about 48%), which sinters at 192 ° C and melts between 196 and 200 ° C. If necessary, the product can be recrystallized from methanol.

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