DIOSMIN PREPARATION METHOD

Abstract

Process for the preparation of diosmin.

Claims

1-13. (canceled)

14. A process for the preparation of diosmin comprising the following steps: a) acetylation of hesperidin, b) oxidation of the acetylated hesperidin to acetylated diosmin by an iodine donor, at a temperature of from 90 to 120° C., 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 acetate, potassium acetate, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium methanolate, andsodium ethanolate, and mixtures thereof, then d) deprotection of the acetylated diosmin to diosmin by heating in the presence of a base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium methanolate, and sodium ethanolate, alone or as a mixture with sodium acetate or potassium acetate, e) purification by base/acid treatment.

15. The process according to claim 14, wherein the diosmin obtained contains other flavonoids.

16. The process according to either claim 15, wherein the diosmin obtained contains less than 0.6% of 6-iododiosmin and less than 3.0% of isorhoifolin.

17. The process according to claim 14, wherein the amount of acetic anhydride is between 8 and 10 molar equivalents relative to the hesperidin used.

18. The process according to claim 14, wherein the acetylation reaction (a) is carried out at a temperature between 40° C. and 135° C.

19. The process according to claim 14, wherein the iodine donor is selected from NaI/H.sub.2O.sub.2, KI/H.sub.2O.sub.2, TBAI/H.sub.2O.sub.2 and NaI/I.sub.2/H.sub.2O.sub.2.

20. The process according to claim 19, wherein the iodine donor is NaI in an amount of from 0.05 to 0.2 molar equivalent relative to the hesperidin used.

21. The process according to claim 14, wherein the amount of hydrogen peroxide is from 1.0 to 1.2 molar equivalents relative to the hesperidin used.

22. The process according to claim 14, wherein the acetylated diosmin obtained at the end of the oxidation step (b) is isolated by precipitation in water before being used in step c).

23. The process according to claim 14, wherein the base used for step c) is sodium hydroxide or potassium hydroxide in aqueous solution, sodium acetate or potassium acetate in aqueous solution, or a mixture of sodium hydroxide or potassium hydroxide and sodium acetate or potassium acetate in aqueous solution.

24. The process according to claim 14, wherein the alcohol used for step c) is methanol, ethanol or isopropanol.

25. The process according to claim 14, wherein the amount of base used in step (c) is between 0.5 and 2.5 molar equivalents relative to the hesperidin used.

26. The process according to claim 14, wherein the amount of base added to the deacetylation step (d) is between 2 and 4.5 molar equivalents relative to the hesperidin used.

Description

EXAMPLE 1: DIOSMIN

[0041] Step A: Acetylated diosmin

[0042] Introduce into a reactor between 20-25° C. potassium acetate (98.6 mmol) and acetic anhydride (2996.2 mmol).

[0043] Heat the suspension, while stirring, to 40° C. then introduce hesperidin (2×163.8 mmol; HPLC titer: 91.3%, isonaringin 3.8%). Continue stirring while heating at 40° C., then heat to 132° C. in 45 min while stirring. The mixture changes to a clear solution at the end of the heating. Stir the solution for 60 min at 132° C. then cool to 105° C.

[0044] Introduce aqueous sodium iodide solution (33 mmol in 20 g of water). At 105° C., pour in hydrogen peroxide 35% (341.5 mmol) stabilised with 0.1% sulfuric acid.

[0045] Stir for 30 min at 105° C. then cool to 100° C. while stirring and precipitate in a beaker containing water (approx. 7 vol), with mechanical stirring at 20-40° C.

[0046] After 30 min of stirring between 20-40° C., filter in vacuo, wash the cake with water (9 vol; then 2×2 vol). Expurge for 16 h in vacuo between 20-25° C.

[0047] Step B: Diosmin

[0048] Introduce into an autoclave the acetylated diosmin obtained in Step A and methanol (3.5 vol). Place under stirring then heat under reflux at a pressure of 5 bar. After 15 min under reflux, introduce sodium hydroxide as a 30% aqueous solution (1.2 mol eq). Heat under reflux for 30 min then cool to 50° C. at normal pressure and introduce sodium hydroxide as a 30% aqueous solution (2.4 mol eq). After 2 h at 50° C., cool to 20° C. then filter and wash the cake with methanol (2×3 vol).

[0049] Dissolve the crude diosmin in 2.5 mol eq of sodium hydroxide and water (2.5 vol) at 20° C.

[0050] Add sulfuric acid to adjust the pH to between 2 and 4. Maintain for 30 min at 20° C., filter, wash twice with water (2×5 vol) and dry. [0051] Yield starting from hesperidin: 83.8% [0052] Purity (HPLC): 90.6% [0053] Content of 6-iododiosmin: 0.3% [0054] Content of isorhoifolin: 2.0%.

EXAMPLE 2: DIOSMIN

[0055] Step A: Acetylated diosmin

[0056] Introduce into a reactor between 20-25° C. potassium acetate (207.1 mmol) and acetic anhydride (6291.9 mmol).

[0057] Heat the suspension, while stirring, to 100° C. then introduce hesperidin (5×137.6 mmol; HPLC titer: 91.7% and isonaringin 3.6%). Continue stirring while heating at 100° C., then heat to 132° C. in 15 min while stirring. The mixture changes to a clear solution at the end of the heating. Stir the solution for 120 min at 132° C. then cool to 105° C.

[0058] Introduce aqueous sodium iodide solution (68.8 mmol in 40 g of water). At 105° C., pour in hydrogen peroxide 35% (717.1 mmol) stabilised with 0.1% sulfuric acid.

[0059] Stir for 30 min at 105° C. then cool to 100° C. while stirring and precipitate in a beaker containing water (approx. 7 vol), with mechanical stirring at 20-40° C.

[0060] After 30 min of stirring between 20-40° C., filter in vacuo, wash the cake with water (9 vol; then 2×2 vol). Expurge for 16 h in vacuo between 20-25° C.

[0061] Step B: Diosmin

[0062] Introduce into an autoclave the acetylated diosmin obtained in Step A and methanol (3.5 vol). Place under stirring then heat under reflux at a pressure of 5 bar. After 15 min under reflux, introduce sodium hydroxide as a 30% aqueous solution (1.55 mol eq). Heat under reflux for 30 min then cool to 50° C. at normal pressure and introduce sodium hydroxide as a 30% aqueous solution (2.4 mol eq). After 2 h at 50° C., cool to 20° C. then filter and wash the cake with methanol (2×3 vol).

[0063] Dissolve the crude diosmin in 2.5 mol eq of sodium hydroxide and water (2.5 vol) at 20° C. Add sulfuric acid to adjust the pH to between 2 and 4. Maintain for 30 min at 20° C., filter, wash twice with water (2×5 vol) and dry. [0064] Yield starting from hesperidin: 81.2% [0065] Purity (HPLC): 90.4% [0066] Content of 6-iododiosmin: 0.29% [0067] Content of isorhoifolin: 2.2%.

EXAMPLE 3: DIOSMIN

[0068] Introduce into an autoclave the acetylated diosmin obtained in Step A of Example 1 and methanol (3.5 vol), add 2 mol eq of an aqueous solution of potassium acetate then heat under reflux at a pressure of from 7 to 8 bar. Next, cool to 50° C. and introduce an aqueous solution of potassium hydroxide (4.2 mol eq). After contact at 50° C., cool to 20° C., then filter and wash with methanol (2×1.5 vol).

[0069] Dissolve the crude diosmin in 2.5 mol eq of sodium hydroxide and water (2.5 vol) at 20° C. Add sulfuric acid to adjust the pH to between 2 and 4. Maintain for 30 min at 20° C., then filter, wash twice with water (2×5 vol) and dry. [0070] Yield starting from hesperidin: 87.7% [0071] Purity (HPLC): 90.1% [0072] Content of 6-iododiosmin: not detected (<0.10%)

EXAMPLE 4: ACETYLATED DIOSMIN WITH DIFFERENT IODINE DONORS

[0073] Into a 25-ml three-necked flask equipped with an ovoid stirrer and a syringe driver, introduce 10 g of hesperidin, 0.5 g of potassium acetate and 14 ml/15.6 g of acetic anhydride. Gradually bring the temperature to 132° C. and leave at 130° C. for 1 h.

[0074] Cool to approximately 90° C. then introduce 0.322 g of sodium iodide or the equivalent iodine donor and 2.258 g of water. Heat to 105° C. then add hydrogen peroxide 35% (1.1835 ml/1.645 g) and 5.161 g of water.

TABLE-US-00002 Test 3a 3b 3c 3d Hesperidin 10 g 2 g 2 g 2 g Acetic 9.146 mol eq 9.146 mol eq 9.146 mol eq 9.146 mol eq anhydride Potassium 0.327 mol eq 0.327 mol eq 0.327 mol eq 0.327 mol eq acetate 35% H.sub.2O.sub.2 1.036 mol eq 1.033 mol eq 1.033 mol eq 1.033 mol eq H.sub.2SO.sub.4 / 0.00109 mol eq 0.00109 mol eq 0.00109 mol eq Iodine donor NaI KI TBAI NaI/I.sub.2 9/1 0.133 mol eq 0.133 mol eq 0.133 mol eq 0.120/0.013 mol eq Acetylated 94% >97% >98% >97% diosmin

EXAMPLE 5: DIOSMIN WITH DIFFERENT BASES

[0075] Introduce into an autoclave the acetylated diosmin obtained in Step A of Example 2 and methanol (3.5 vol). Place under stirring then heat under reflux at a pressure of 7 bar. After 15 min under reflux, introduce the base as a 30% aqueous solution (1.2 mol eq). Heat under reflux for 30 min then cool to 50° C. at normal pressure and introduce the base as a 30% aqueous solution (2.4 mol eq). After 2 h at 50° C., cool to 20° C. then filter and wash the cake with methanol (2×3 vol).

TABLE-US-00003 Test 4a 4b 4c 4d 4e Base CH.sub.3ONa NaOH LiOH KOH K.sub.2CO.sub.3 Yield/Hesperidin used   84%   84%   85%   84%   80% Diosmin 89.8% 90.9% 90.4% 90.8% 92.4% Isorhoifolin  2.6%  2.0%  2.1%  2.0%  2.1% 6-Iododiosmin 0.45% 0.46% 0.42% 0.62% 0.54%

EXAMPLE 6 (COMPARATIVE): REPRODUCTION OF THE PROCESS OF WO 2016/124585

[0076] 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 a reactor. The reaction medium is then heated to 115-120° C., maintaining this temperature for one hour approximately, and then the medium is cooled to 60-70° C.

[0077] A solution of sodium iodide (0.9 g) in water (6 ml) is added, and the reaction medium is heated to reflux. Then, a solution of 35 ml of 5.4% (by mass) hydrogen peroxide stabilised with sulfuric acid is added to the reaction medium, while maintaining the reflux. Next, the reaction medium is cooled to 40-50° C. and potassium hydroxide (10 g) is added to the reaction mixture; the pH is then 4. The mixture is then heated at 115-120° C. for 3 hours, and then cooled to 30° C.

[0078] The reaction mixture is added to a reactor containing a 2N aqueous sodium hydroxide solution (300 ml). After 1 h and 30 min, sulfuric acid is added until the pH reaches 7.5. The precipitate is then filtered and washed with water, to obtain wet crude diosmin.

[0079] The crude diosmin thus obtained is crystallised by dissolving it in an aqueous solution of sodium hydroxide, then by acidifying it with sulfuric acid until the product precipitates.

[0080] The solid is filtered, washed with water and dried.

[0081] Analysis (HPLC):

TABLE-US-00004 Percentage in Diosmin the product specifications of (European Substances Example 5 Pharmacopoeia) Diosmin 87.1% 90.0 to 102.0% Isorhoifolin  3.6% <3.0% 6-Iododiosmin 0.99% <0.6%