Process for the preparation of diosmin
The present invention relates to a process for the preparation of diosmin from hesperidin. The process involves the oxidation of acylated hesperidin with iodine or bromine in a C 2 -C 4 carboxylic acid medium and subsequent treatment with an inorganic base to partially neutralize the acidic media. The process allows obtaining diosmin with low iodine or bromine content, avoiding the use of organic solvents.
1. Process for the preparation of diosmin from hesperidin comprising the following steps:
a) acylating hesperidin with the anhydride of a C2-C4 carboxylic acid;
b) treating the mixture obtained in step a) with a halogen selected from iodine and bromine, in aqueous medium;
c) treating the mixture obtained in step b) with an inorganic base to reach a pH value in the range 3.5-6.5;
d) deacylating the acylated diosmin obtained in step c) by treatment with an inorganic base;
wherein no organic solvent is added throughout the process, and
wherein the diosmin has a halogen content of less than 1000 ppm and is free from residual organic solvents.
2. Process according to claim 1 , wherein in step a) a catalyst is used selected from sodium acetate and potassium acetate.
3. Process according to claim 1 , wherein the anhydride of the C2-C4 carboxylic acid of step a) is acetic anhydride.
4. Process according to claim 1 , wherein step b) is carried out by
a) using the halogen in a stoichiometric amount, or
b) using a halide in a stoichiometric amount and an oxidant in a stoichiometric amount, or
c) using the halogen in a catalytic amount and an oxidant in a stoichiometric amount.
5. Process according to claim 1 , wherein step b) is carried out by using a halide in a catalytic amount and an oxidant in a stoichiometric amount.
6. Process according to claim 4 , wherein the oxidant is selected from the group of hydrogen peroxide, sodium percarbonate, potassium percarbonate, sodium perborate, potassium perborate, sodium permanganate, potassium permanganate, sodium dichromate, potassium dichromate, and hydrates thereof.
7. Process according to claim 6 , wherein the oxidant is hydrogen peroxide.
8. Process according to claim 6 , wherein the oxidant is selected from sodium percarbonate, potassium percarbonate, sodium perborate, potassium perborate and hydrates thereof.
9. Process according to claim 4 , wherein the iodide is selected from sodium iodide, potassium iodide, calcium iodide, magnesium iodide and mixtures thereof.
10. Process according to claim 9 , wherein the iodide is selected from sodium iodide, potassium iodide and mixtures thereof.
11. Process according to claim 4 , wherein the bromide is selected from sodium bromide, potassium bromide, calcium bromide, magnesium bromide, and mixtures thereof.
12. Process according to claim 1 , wherein the inorganic base of step c) is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, hydrates thereof, and mixtures thereof.
13. Process according to claim 12 , wherein the inorganic base is selected from sodium hydroxide, potassium hydroxide and mixtures thereof.
14. Process according to claim 1 , wherein in step c) the pH value is in the range of 4.5-5.5.
15. Process according to claim 1 , wherein the diosmin obtained after step d) is recrystallized in aqueous media.
16. Diosmin obtainable by the process of claim 1 ,
wherein the diosmin has a halogen content of less than 1000 ppm and is free from residual organic solvents.
17. Process according to claim 2 , wherein the anhydride of the C2-C4 carboxylic acid of step a) is acetic anhydride.
18. Process according to claim 2 , wherein step b) is carried out by
a) using the halogen in a stoichiometric amount, or
b) using a halide in a stoichiometric amount and an oxidant in a stoichiometric amount, or
c) using the halogen in a catalytic amount and an oxidant in a stoichiometric amount.
19. Process according to claim 3 , wherein step b) is carried out by
a) using the halogen in a stoichiometric amount, or
b) using a halide in a stoichiometric amount and an oxidant in a stoichiometric amount, or
c) using the halogen in a catalytic amount and an oxidant in a stoichiometric amount.