Preparation method of diosmin

Abstract

The present invention relates to a preparation method of diosmin.

Description

[0001] The present invention relates to a preparation method of diosmin.

[0002] Diosmin is a compound of formula (I):

[0003]

[0004] Diosmin is used to treat venous diseases such as chronic venous insufficiency or haemorrhoidal diseases.

[0005] It is also Micronized Purified Flavonoid Fraction or MPFF The main ingredient.

[0006] Diosmin is synthesized by oxidation of hesperidin. Hesperidin is a compound of formula (II):

[0007]

[0008] Hesperidin is obtained from natural substances (oranges). The diversity of oranges used results in hesperidin of unequal purity, containing other flavonoids in variable amounts. In particular, hesperidin may contain up to 4% isonaringin, which is converted to isonaringin by oxidation.

[0009] Therefore, diosmin usually contains other flavonoids, some of which originate from the oxidation of the flavonoids present in the original hesperidin and others of which are reaction by-products.

[0010] Considering the pharmaceutical value of diosmin, it is necessary to obtain diosmin with excellent yield and desired purity regardless of the source of hesperidin.

[0011] The specifications specified in the European Pharmacopoeia are as follows:

[0012]

[0013]

[0014] In particular, it is necessary that the obtained diosmin contains less than 0.6% of 6-iododiosmin and less than 3.0% of isoaraxin.

[0015] The preparation of diosmin from hesperidin has been described in the literature.

[0016] FR2311028 describes a method for obtaining diosmin by acetylation of hesperidin followed by oxidation of the acetylated hesperidin by bromination, alkaline hydrolysis and separation. The crude diosmin thus obtained is purified by a re-treatment step using pyridine.

[0017] This method is not ideal because the yield is only 65%. In addition, it uses pyridine, a Class 3 carcinogenic solvent.

[0018] Patent application WO2016 / 124585 has the advantage of not using an organic solvent such as pyridine. However, when the hesperidin used contains a large amount of isonaringin, the method described therein cannot obtain diosmin with the desired purity.

[0019] One problem of the present invention is to minimize the content of 6-iododiosmin in the resulting diosmin without using a Class 3 solvent such as pyridine.

[0020] Another problem of the present invention is to minimize the isonaringin content in the obtained diosmin without using class 3 solvents such as pyridine while starting from hesperidin containing up to 4% isonaringin.

[0021] More specifically, the present invention relates to a method for preparing diosmin by

[0022] a) Acetylation reaction of hesperidin,

[0023] b) oxidizing acetylated hesperidin to acetylated diosmin at 90-120° C. by an iodine donor,

[0024] c) heating the acetylated diosmin in an autoclave at a pressure of 5 to 8 bar under reflux of an alcohol such as methanol, ethanol or isopropanol in the presence of a base selected from sodium or potassium acetate, sodium, potassium or lithium hydroxide, potassium carbonate, sodium methoxide or sodium ethoxide, either alone or as a mixture with another of these bases, and then

[0025] d) deprotecting acetylated diosmin to diosmin by heating in the presence of a base selected from sodium hydroxide, potassium hydroxide or lithium hydroxide, potassium carbonate, sodium methoxide or sodium ethoxide, either alone or as a mixture with sodium acetate or potassium acetate,

[0026] e) Purification by alkaline / acid treatment.

[0027] According to one embodiment of the present invention, the obtained diosmin contains other flavonoids, such as hesperidin, isorhinin, montanin or diosminin.

[0028] According to one embodiment of the present invention, the acetylation step (a) is performed by reacting hesperidin with acetic anhydride and potassium or sodium acetate.

[0029] The acetylation reaction is preferably carried out at a temperature of 40°C to 135°C.

[0030] The amount of acetic anhydride is preferably 8 to 10 molar equivalents relative to the hesperidin used.

[0031] The iodine donor used in the oxidation step (b) is preferably selected from NaI / H 2 O 2 KI / H 2 O 2 TBAI / H 2 O 2 andNaI / I 2 (Preferred 9 / 1) / H 2 O 2 .

[0032] The amount of NaI is preferably 0.05-0.20 molar equivalent relative to the hesperidin used.

[0033] The amount of hydrogen peroxide is preferably 1.0 to 1.2 molar equivalents relative to the hesperidin used.

[0034] According to one embodiment of the invention, the acetylated diosmin obtained at the end of oxidation step (b) is isolated, preferably by precipitation in water, before being used in step c).

[0035] According to one embodiment of the present invention, the base used in step c) is an aqueous solution of sodium hydroxide or potassium hydroxide, an aqueous solution of sodium acetate or potassium acetate, or a mixture of sodium hydroxide or potassium hydroxide and sodium acetate or potassium acetate in aqueous solution.

[0036] The sodium acetate or potassium acetate used in step c) can be generated in situ by neutralizing the residual acetic acid present in the acetylated diosmin with sodium hydroxide or potassium hydroxide.

[0037] The amount of the base used in step (c) is preferably 0.5 to 2.5 molar equivalents relative to the hesperidin used.

[0038] According to one embodiment of the present invention, the base added to the deacetylation step (d) is sodium hydroxide or potassium hydroxide.

[0039] The amount of the base added to the deacetylation step (d) is preferably 2 to 4.5 molar equivalents relative to the hesperidin used.

[0040] According to one embodiment of the invention, the alkali / acid treatment (step e) is carried out by dissolution in water in the presence of a base such as sodium hydroxide followed by precipitation by salt formation with an acid such as sulfuric acid.

[0041] The following examples illustrate the invention.

[0042] abbreviation :

[0043] mol eq molar equivalent (relative to hesperidin)

[0044] HPLC High Performance Liquid Chromatography

[0045] m / m represents the ratio of mass / mass

[0046] TBAI Tetra-n-butylammonium iodide

[0047] vol Volume equivalent (relative to hesperidin)

[0048] Example 1 :Diosmin

[0049] Step A acetylated diosmin

[0050] Potassium acetate (98.6 mmol) and acetic anhydride (2996.2 mmol) were introduced into the reactor at 20-25 °C.

[0051] The suspension was heated to 40°C with stirring, and then hesperidin (2×163.8 mmol; HPLC titer: 91.3%, isonaringin 3.8%) was added. Stirring was continued while heating at 40°C, and then heated to 132°C within 45 minutes while stirring. At the end of heating, the mixture became a clear solution. The solution was stirred at 132°C for 60 minutes and then cooled to 105°C.

[0052] Sodium iodide aqueous solution (33 mmol in 20 g of water) was added. 35% hydrogen peroxide (341.5 mmol) stabilized with 0.1% sulfuric acid was poured in at 105°C.

[0053] Stir at 105°C for 30 minutes, then cool to 100°C with stirring, stir and precipitate in a beaker containing water (about 7 volumes) at 20-40°C with mechanical stirring.

[0054] After stirring at 20-40°C for 30 minutes, vacuum filter and wash the filter cake with water (9 volumes; then 2 x 2 volumes). Expurge under vacuum at 20-25°C for 16 hours.

[0055] Step B :Diosmin

[0056] The acetylated diosmin obtained in step A and methanol (3.5 volumes) are introduced into an autoclave. Place under stirring and then heat to reflux at 5 bar pressure. After reflux for 15 minutes, sodium hydroxide (1.2 molar equivalents) is added as a 30% aqueous solution. Heating under reflux for 30 minutes, then cooling to 50°C at normal pressure and adding sodium hydroxide (2.4 molar equivalents) as a 30% aqueous solution. After 2 hours at 50°C, cool to 20°C and then filter, washing the filter cake with methanol (2×3 volumes).

[0057] Crude diosmin was dissolved in 2.5 molar equivalents of sodium hydroxide and water (2.5 volumes) at 20°C.

[0058] The pH was adjusted to 2-4 by adding sulfuric acid, maintained at 20°C for 30 minutes, filtered, washed twice with water (2 x 5 volumes), and dried.

[0059] Yield from hesperidin: 83.8%

[0060] Purity (HPLC): 90.6%

[0061] Content of 6-iododiosmin: 0.3%

[0062] Content of isobarbitalin: 2.0%.

[0063] Example 2 :Diosmin

[0064] Step A acetylated diosmin

[0065] Potassium acetate (207.1 mmol) and acetic anhydride (6291.9 mmol) were introduced into the reactor at 20-25 °C.

[0066] The suspension was heated to 100° C. under stirring, and then hesperidin (5×137.6 mmol; HPLC titer: 91.7% and isonaringin 3.6%) was added. Stirring was continued while heating to 100° C., and then heated to 132° C. within 15 minutes while stirring. At the end of heating, the mixture became a clear solution. The solution was stirred at 132° C. for 120 minutes and then cooled to 105° C.

[0067] Sodium iodide aqueous solution (68.8 mmol in 40 g water) was added. At 105°C, 35% hydrogen peroxide (717.1 mmol) stabilized with 0.1% sulfuric acid was poured in.

[0068] Stir at 105°C for 30 minutes, then cool to 100°C with stirring, stir and precipitate in a beaker containing water (about 7 volumes) at 20-40°C with mechanical stirring.

[0069] After stirring at 20-40°C for 30 minutes, vacuum filter and wash the filter cake with water (9 volumes; then 2 x 2 volumes). Purify under vacuum at 20-25°C for 16 hours.

[0070] Step B :Diosmin

[0071] The acetylated diosmin obtained in step A and methanol (3.5 volumes) are introduced into an autoclave. Place under stirring and then heat to reflux at 5 bar pressure. After reflux for 15 minutes, sodium hydroxide (1.55 molar equivalents) is added as a 30% aqueous solution. Heating under reflux for 30 minutes, then cooling to 50°C at normal pressure and adding sodium hydroxide (2.4 molar equivalents) as a 30% aqueous solution. After 2 hours at 50°C, cool to 20°C and then filter, washing the filter cake with methanol (2×3 volumes).

[0072] Crude diosmin was dissolved in 2.5 molar equivalents of sodium hydroxide and water (2.5 volumes) at 20°C.

[0073] The pH was adjusted to 2-4 by adding sulfuric acid, maintained at 20°C for 30 minutes, filtered, washed twice with water (2 x 5 volumes), and dried.

[0074] Yield from hesperidin: 81.2%

[0075] Purity (HPLC): 90.4%

[0076] Content of 6-iododiosmin: 0.29%

[0077] Content of isobarbitalin: 2.2%.

[0078] Example 3 :Diosmin

[0079] The autoclave was charged with acetylated diosmin obtained in step A of Example 1 and methanol (3.5 volumes), and 2 molar equivalents of potassium acetate aqueous solution were added, followed by heating to reflux at a pressure of 7-8 bar. Then, it was cooled to 50° C., and potassium hydroxide aqueous solution (4.2 molar equivalents) was added. After contacting at 50° C., it was cooled to 20° C., then filtered, and washed with methanol (2×1.5 volumes).

[0080] Crude diosmin was dissolved in 2.5 molar equivalents of sodium hydroxide and water (2.5 volumes) at 20°C.

[0081] Sulfuric acid was added to adjust the pH to 2-4, maintained at 20°C for 30 minutes, then filtered, washed twice with water (2 x 5 volumes), and dried.

[0082] Yield from hesperidin: 87.7%

[0083] Purity (HPLC): 90.1%

[0084] Content of 6-iododiosmin: Not detected (<0.10%)

[0085] Example 4 : Acetylated diosmin using different iodine donors

[0086] Into a 25 mL three-necked flask equipped with an oval stirrer and a syringe driver, 10 g of hesperidin, 0.5 g of potassium acetate and 14 ml / 15.6 g of acetic anhydride were introduced. The temperature was gradually raised to 132° C. and left at 130° C. for 1 hour.

[0087] Cool to about 90°C and then add 0.322 g of sodium iodide or an equivalent iodine donor and 2.258 g of water.

[0088] Heat to 105°C, then add hydrogen peroxide 35% (1.1835 ml / 1.645 g) and 5.161 g water.

[0089]

[0090] Example 5 :Diosmin using different bases

[0091] The acetylated diosmin obtained in step A of example 2 and methanol (3.5 volumes) are introduced into an autoclave. Place under stirring and then heat to reflux at 7 bar pressure. After reflux for 15 minutes, base (1.2 molar equivalents) is added as a 30% aqueous solution. Reflux is heated for 30 minutes, then cooled to 50°C at normal pressure and base (2.4 molar equivalents) is added as a 30% aqueous solution. After 2 hours at 50°C, cool to 20°C and then filter, washing the filter cake with methanol (2 x 3 volumes).

[0092] test 4a 4b 4c 4d 4e Alkali <![CDATA[CH 3 ON]]> NaOH LiOH KOH <![CDATA[K 2 CO 3 ]]> Yield / Hesperidin used 84％ 84％ 85％ 84％ 80％ Diosmin 89.8％ 90.9％ 90.4％ 90.8％ 92.4％ Isobarbin 2.6％ 2.0％ 2.1％ 2.0％ 2.1％ 6-Iodidiosmin 0.45％ 0.46％ 0.42％ 0.62％ 0.54％

[0093] Example 6 (Comparison): Reproduction of the method of WO 2016 / 124585

[0094] 40 g of acetic anhydride, 0.75 g of potassium acetate and 30 g of hesperidin (purity 91.3%; isonaringin 3.8%) are introduced into the reactor. The reaction medium is then heated to 115-120° C., maintained at this temperature for about one hour, and then cooled to 60-70° C.

[0095] A solution of sodium iodide (0.9 g) in water (6 ml) is added and the reaction medium is heated to reflux. Then, 35 ml of a 5.4% (by mass) hydrogen peroxide solution stabilized with sulfuric acid are added to the reaction medium while maintaining reflux. Next, the reaction medium is cooled to 40-50° C. and potassium hydroxide (10 g) is added to the reaction mixture; the pH value is then 4. The mixture is then heated at 115-120° C. for 3 hours and then cooled to 30° C.

[0096] The reaction mixture was added to a reactor containing 2N sodium hydroxide aqueous solution (300 ml). After 1 hour and 30 minutes, sulfuric acid was added until the pH reached 7.5. The precipitate was then filtered and washed with water to obtain wet crude diosmin.

[0097] The crude diosmin thus obtained was crystallized by dissolving it in aqueous sodium hydroxide solution and then acidifying with sulfuric acid until the product precipitated. The solid was filtered, washed with water and dried. Analysis (HPLC):

[0098] substance Example 5 Product Percentage Diosmin Specifications (European Pharmacopoeia) Diosmin 87.1％ 90.0 to 102.0% Isobarbin 3.6％ <3.0％ 6-Iodidiosmin 0.99％ <0.6％

Claims

1. A method for preparing diosmin, which is carried out by: a) Acetylation reaction of hesperidin, b) oxidizing acetylated hesperidin to acetylated diosmin at 90-120° C. by an iodine donor, c) heating the acetylated diosmin in an autoclave at a pressure of 5 to 8 bar under reflux of an alcohol in the presence of a base selected from sodium or potassium acetate, sodium, potassium or lithium hydroxide, potassium carbonate, sodium methoxide or sodium ethoxide, either alone or as a mixture with another of these bases, and then d) deprotecting acetylated diosmin to diosmin by heating in the presence of a base selected from sodium hydroxide, potassium hydroxide or lithium hydroxide, potassium carbonate, sodium methoxide or sodium ethoxide, either alone or as a mixture with sodium acetate or potassium acetate, e) Purification by alkaline / acid treatment.

2. The method according to claim 1, wherein the diosmin obtained contains other flavonoids.

3. The method according to claim 1, wherein the obtained diosmin contains less than 0.6% of 6-iododiosmin and less than 3.0% of isobarbital.

4. The method according to claim 2, wherein the obtained diosmin contains less than 0.6% of 6-iododiosmin and less than 3.0% of isobarbital.

5. The method according to claim 1, wherein the acetylation step (a) is carried out by reacting hesperidin with acetic anhydride and potassium or sodium acetate, and the amount of acetic anhydride is 8 to 10 molar equivalents relative to the hesperidin used.

6. The method according to claim 2, wherein the acetylation step (a) is carried out by reacting hesperidin with acetic anhydride and potassium or sodium acetate, and the amount of acetic anhydride is 8 to 10 molar equivalents relative to the hesperidin used.

7. The method according to claim 3, wherein the acetylation step (a) is carried out by reacting hesperidin with acetic anhydride and potassium or sodium acetate, and the amount of acetic anhydride is 8 to 10 molar equivalents relative to the hesperidin used.

8. The method according to claim 4, wherein the acetylation step (a) is carried out by reacting hesperidin with acetic anhydride and potassium or sodium acetate, and the amount of acetic anhydride is 8 to 10 molar equivalents relative to the hesperidin used.

9. The method according to claim 1, wherein the acetylation reaction (a) is performed at a temperature of 40°C to 135°C.

10. The method according to claim 2, wherein the acetylation reaction (a) is performed at a temperature of 40°C to 135°C.

11. The method according to claim 3, wherein the acetylation reaction (a) is performed at a temperature of 40°C to 135°C.

12. The method according to claim 4, wherein the acetylation reaction (a) is performed at a temperature of 40°C to 135°C.

13. The method according to claim 5, wherein the acetylation reaction (a) is performed at a temperature of 40°C to 135°C.

14. The method according to claim 6, wherein the acetylation reaction (a) is performed at a temperature of 40°C to 135°C.

15. The method according to claim 7, wherein the acetylation reaction (a) is performed at a temperature of 40°C to 135°C.

16. The method according to claim 8, wherein the acetylation reaction (a) is performed at a temperature of 40°C to 135°C.

17. The method according to claim 1, wherein the iodine donor is selected from NaI / H 2 O 2 KI / H 2 O 2 TBAI / H 2 O 2 andNaI / I 2 / H 2 O 2 .

18. The method according to claim 2, wherein the iodine donor is selected from NaI / H 2 O 2 KI / H 2 O 2 TBAI / H 2 O 2 andNaI / I 2 / H 2 O 2 .

19. The method according to claim 3, wherein the iodine donor is selected from NaI / H 2 O 2 KI / H 2 O 2 TBAI / H 2 O 2 andNaI / I 2 / H 2 O 2 .

20. The method according to claim 4, wherein the iodine donor is selected from NaI / H 2 O 2 KI / H 2 O 2 TBAI / H 2 O 2 andNaI / I 2 / H 2 O 2 .

21. The method according to claim 5, wherein the iodine donor is selected from NaI / H 2 O 2 KI / H 2 O 2 TBAI / H 2 O 2 andNaI / I 2 / H 2 O 2 .

22. The method according to claim 6, wherein the iodine donor is selected from NaI / H 2 O 2 KI / H 2 O 2 TBAI / H 2 O 2 andNaI / I 2 / H 2 O 2 .

23. The method according to claim 7, wherein the iodine donor is selected from NaI / H 2 O 2 KI / H 2 O 2 TBAI / H 2 O 2 andNaI / I 2 / H 2 O 2 .

24. The method according to claim 8, wherein the iodine donor is selected from NaI / H 2 O 2 KI / H 2 O 2 TBAI / H 2 O 2 andNaI / I 2 / H 2 O 2 .

25. The method according to claim 9, wherein the iodine donor is selected from NaI / H 2 O 2 KI / H 2 O 2 TBAI / H 2 O 2 andNaI / I 2 / H 2 O 2 .

26. The method according to claim 10, wherein the iodine donor is selected from NaI / H 2 O 2 KI / H 2 O 2 TBAI / H 2 O 2 andNaI / I 2 / H 2 O 2 .

27. The method according to claim 11, wherein the iodine donor is selected from NaI / H 2 O 2 KI / H 2 O 2 TBAI / H 2 O 2 andNaI / I 2 / H 2 O 2 .

28. The method according to claim 12, wherein the iodine donor is selected from NaI / H 2 O 2 KI / H 2 O 2 TBAI / H 2 O 2 andNaI / I 2 / H 2 O 2 .

29. The method according to claim 13, wherein the iodine donor is selected from NaI / H 2 O 2 KI / H 2 O 2 TBAI / H 2 O 2 andNaI / I 2 / H 2 O 2 .

30. The method according to claim 14, wherein the iodine donor is selected from NaI / H 2 O 2 KI / H 2 O 2 TBAI / H 2 O 2 andNaI / I 2 / H 2 O 2 .

31. The method according to claim 15, wherein the iodine donor is selected from NaI / H 2 O 2 KI / H 2 O 2 TBAI / H 2 O 2 andNaI / I 2 / H 2 O 2 .

32. The method according to claim 16, wherein the iodine donor is selected from NaI / H 2 O 2 KI / H 2 O 2 TBAI / H 2 O 2 andNaI / I 2 / H 2 O 2 .

33. The method according to claim 17, wherein the iodine donor is NaI in an amount of 0.05 to 0.2 molar equivalents relative to the hesperidin used.

34. The method according to claim 18, wherein the iodine donor is NaI in an amount of 0.05 to 0.2 molar equivalents relative to the hesperidin used.

35. The method according to claim 19, wherein the iodine donor is NaI in an amount of 0.05 to 0.2 molar equivalents relative to the hesperidin used.

36. The method according to claim 20, wherein the iodine donor is NaI in an amount of 0.05 to 0.2 molar equivalents relative to the hesperidin used.

37. The method according to claim 21, wherein the iodine donor is NaI in an amount of 0.05 to 0.2 molar equivalents relative to the hesperidin used.

38. The method according to claim 22, wherein the iodine donor is NaI in an amount of 0.05 to 0.2 molar equivalents relative to the hesperidin used.

39. The method according to claim 23, wherein the iodine donor is NaI in an amount of 0.05 to 0.2 molar equivalents relative to the hesperidin used.

40. The method according to claim 24, wherein the iodine donor is NaI in an amount of 0.05 to 0.2 molar equivalents relative to the hesperidin used.

41. The method according to claim 25, wherein the iodine donor is NaI in an amount of 0.05 to 0.2 molar equivalents relative to the hesperidin used.

42. The method according to claim 26, wherein the iodine donor is NaI in an amount of 0.05 to 0.2 molar equivalents relative to the hesperidin used.

43. The method according to claim 27, wherein the iodine donor is NaI in an amount of 0.05 to 0.2 molar equivalents relative to the hesperidin used.

44. The method according to claim 28, wherein the iodine donor is NaI in an amount of 0.05 to 0.2 molar equivalents relative to the hesperidin used.

45. The method according to claim 29, wherein the iodine donor is NaI in an amount of 0.05 to 0.2 molar equivalents relative to the hesperidin used.

46. ​​The method according to claim 30, wherein the iodine donor is NaI in an amount of 0.05 to 0.2 molar equivalents relative to the hesperidin used.

47. The method according to claim 31, wherein the iodine donor is NaI in an amount of 0.05 to 0.2 molar equivalents relative to the hesperidin used.

48. The method according to claim 32, wherein the iodine donor is NaI in an amount of 0.05 to 0.2 molar equivalents relative to the hesperidin used.

49. The method of claim 17, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

50. The method of claim 18, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

51. The method of claim 19, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

52. The method of claim 20, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

53. The method of claim 21, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

54. The method of claim 22, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

55. The method of claim 23, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

56. The method of claim 24, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

57. The method of claim 25, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

58. The method of claim 26, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

59. The method of claim 27, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

60. The method of claim 28, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

61. The method of claim 29, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

62. The method of claim 30, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

63. The method of claim 31, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

64. The method of claim 32, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

65. The method of claim 33, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

66. The method of claim 34, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

67. The method of claim 35, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

68. The method of claim 36, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

69. The method of claim 37, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

70. The method of claim 38, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

71. The method of claim 39, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

72. The method of claim 40, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

73. The method of claim 41, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

74. The method of claim 42, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

75. The method of claim 43, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

76. The method of claim 44, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

77. The method of claim 45, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

78. The method of claim 46, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

79. The method of claim 47, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

80. The method of claim 48, wherein the amount of hydrogen peroxide is 1.0 to 1.2 molar equivalents relative to the hesperidin used.

81. Process according to any one of claims 1 to 80, wherein the acetylated diosmin obtained at the end of oxidation step (b) is isolated by precipitation in water before being used in step c).

82. The process of any one of claims 1 to 80, wherein the base used in step c) is an aqueous solution of sodium or potassium hydroxide, an aqueous solution of sodium or potassium acetate, or a mixture of sodium or potassium hydroxide and an aqueous solution of sodium or potassium acetate.

83. The process of claim 81, wherein the base used in step c) is an aqueous solution of sodium hydroxide or potassium hydroxide, an aqueous solution of sodium acetate or potassium acetate, or a mixture of sodium hydroxide or potassium hydroxide and an aqueous solution of sodium acetate or potassium acetate.

84. The process according to any one of claims 1 to 80, wherein the alcohol used in step c) is methanol, ethanol or isopropanol.

85. The process of claim 81, wherein the alcohol used in step c) is methanol, ethanol or isopropanol.

86. The process of claim 82, wherein the alcohol used in step c) is methanol, ethanol or isopropanol.

87. The process of claim 83, wherein the alcohol used in step c) is methanol, ethanol or isopropanol.

88. The process according to any one of claims 1 to 80, wherein the amount of base used in step (c) is 0.5 to 2.5 molar equivalents relative to the hesperidin used.

89. The method of claim 81, wherein the amount of base used in step (c) is 0.5 to 2.5 molar equivalents relative to the hesperidin used.

90. The method of claim 82, wherein the amount of base used in step (c) is 0.5 to 2.5 molar equivalents relative to the hesperidin used.

91. The method of claim 83, wherein the amount of base used in step (c) is 0.5 to 2.5 molar equivalents relative to the hesperidin used.

92. The method of claim 84, wherein the amount of base used in step (c) is 0.5 to 2.5 molar equivalents relative to the hesperidin used.

93. The method of claim 85, wherein the amount of base used in step (c) is 0.5 to 2.5 molar equivalents relative to the hesperidin used.

94. The method of claim 86, wherein the amount of base used in step (c) is 0.5 to 2.5 molar equivalents relative to the hesperidin used.

95. The method of claim 87, wherein the amount of base used in step (c) is 0.5 to 2.5 molar equivalents relative to the hesperidin used.

96. The process according to any one of claims 1 to 80, wherein the amount of base added to the deacetylation step (d) is 2 to 4.5 molar equivalents relative to the hesperidin used.

97. The process of claim 81, wherein the amount of base added to the deacetylation step (d) is 2 to 4.5 molar equivalents relative to the hesperidin used.

98. The process of claim 82, wherein the amount of base added to the deacetylation step (d) is 2 to 4.5 molar equivalents relative to the hesperidin used.

99. The process of claim 83, wherein the amount of base added to the deacetylation step (d) is 2 to 4.5 molar equivalents relative to the hesperidin used.

100. The process of claim 84, wherein the amount of base added to the deacetylation step (d) is 2 to 4.5 molar equivalents relative to the hesperidin used.

101. The process of claim 85, wherein the amount of base added to the deacetylation step (d) is 2 to 4.5 molar equivalents relative to the hesperidin used.

102. The process of claim 86, wherein the amount of base added to the deacetylation step (d) is 2 to 4.5 molar equivalents relative to the hesperidin used.

103. The process of claim 87, wherein the amount of base added to the deacetylation step (d) is 2 to 4.5 molar equivalents relative to the hesperidin used.

104. The process of claim 88, wherein the amount of base added to the deacetylation step (d) is 2 to 4.5 molar equivalents relative to the hesperidin used.

105. The process of claim 89, wherein the amount of base added to the deacetylation step (d) is 2 to 4.5 molar equivalents relative to the hesperidin used.

106. The process of claim 90, wherein the amount of base added to the deacetylation step (d) is 2 to 4.5 molar equivalents relative to the hesperidin used.

107. The process of claim 91, wherein the amount of base added to the deacetylation step (d) is 2 to 4.5 molar equivalents relative to the hesperidin used.

108. The process of claim 92, wherein the amount of base added to the deacetylation step (d) is 2 to 4.5 molar equivalents relative to the hesperidin used.

109. The process of claim 93, wherein the amount of base added to the deacetylation step (d) is 2 to 4.5 molar equivalents relative to the hesperidin used.

110. The process of claim 94, wherein the amount of base added to the deacetylation step (d) is 2 to 4.5 molar equivalents relative to the hesperidin used.

111. The process of claim 95, wherein the amount of base added to the deacetylation step (d) is 2 to 4.5 molar equivalents relative to the hesperidin used.

Images